Carboxylic acid amides, the preparation thereof and their use as medicaments

ABSTRACT

The present invention relates to new substituted carboxylic acid amides of general formula 
                         
wherein A, B and R 1  to R 5  are defined as in claim  1 , the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties.

This application is a divisional of U.S. Ser. No. 12/958,882 filed Dec. 2, 2010, which is a divisional of U.S. Ser. No. 11/960,222 filed Dec. 19, 2007, which claims priority to U.S. Ser. No. 11/056,413, filed Feb. 11, 2005, which claims priority to German Application DE 10 2004 009 835, filed on Feb. 28, 2004 and to German Application DE 10 2004 060 984, filed on Dec. 18, 2004, each of which is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to new substituted carboxylic acid amides of general formula

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties.

The compounds of the above general formula I as well as the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, and their stereoisomers have valuable pharmacological properties, particularly an antithrombotic activity and a factor Xa-inhibiting activity.

The present application thus relates to the new compounds of the above general formula I, the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, the preparation and use thereof.

In the above general formula in a first embodiment

A denotes a group of general formula

wherein

-   m denotes the number 1 or 2, -   R^(6a) independently of one another denotes a hydrogen, fluorine,     chlorine or bromine atom or a C₁₋₃-alkyl, hydroxy, amino,     C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl,     C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or     C₁₋₃-alkylcarbonylamino group and -   R^(6b) independently of one another may be a hydrogen atom, a     C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkyloxycarbonyl or     C₁₋₃-alkylsulphonyl group, with the proviso that     -   in the above-mentioned substituted 5- to 7-membered groups A the         heteroatoms optionally introduced as substituents are not         separated from another heteroatom by precisely one carbon atom,         or

a group of general formula

wherein

-   -   m denotes the number 1 or 2,     -   X¹ denotes an oxygen atom or a methylene, —NR^(6b)—, carbonyl or         sulphonyl group,     -   X² denotes an oxygen atom or a —NR^(6b) group,     -   X³ denotes a methylene, carbonyl or sulphonyl group,     -   X⁴ denotes an oxygen or sulphur atom, a —NR^(6b) or carbonyl         group,     -   X⁵ denotes a carbonyl or sulphonyl group,     -   X⁶ denotes an oxygen atom, a —NR^(6b) or methylene group,     -   X⁷ denotes an oxygen or sulphur atom or a —NR^(6b) group,     -   X⁸ denotes a methylene or carbonyl group,     -   X⁹ denotes a —NR^(6b) or carbonyl group,     -   X¹⁰ denotes a sulphinyl or sulphonyl group and     -   R^(6a) independently of one another denote a hydrogen, fluorine,         chlorine or bromine atom or a C₁₋₃-alkyl, hydroxy, amino,         C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl,         C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or         C₁₋₃-alkylcarbonylamino group and     -   R^(6b) independently of one another may be a hydrogen atom, a         C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or         C₁₋₃-alkylsulphonyl group, with the proviso that         -   in the above-mentioned substituted 5- to 7-membered groups A             the heteroatoms optionally introduced as substituents are             not separated from another heteroatom by precisely one             carbon atom,

-   R¹ denotes a hydrogen, fluorine, chlorine or bromine atom, a     C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partly     replaced by fluorine atoms, a C₂₋₃-alkenyl, C₂₋₃-alkynyl, nitro,     amino, C₁₋₃-alkoxy, a mono-, di- or trifluoromethoxy group,

-   R² denotes a hydrogen, fluorine, chlorine or bromine atom or a     C₁₋₃-alkyl group,

-   R³ denotes a hydrogen atom, a C₂₋₃-alkenyl or C₂₋₃-alkynyl group or     a straight-chain or branched C₁₋₆-alkyl group wherein the hydrogen     atoms may be wholly or partly replaced by fluorine atoms, and which     is optionally substituted by a nitrile, hydroxy, a C₁₋₆-alkyloxy     group wherein the hydrogen atoms may be wholly or partly replaced by     fluorine atoms, an allyloxy, propargyloxy, benzyloxy,     C₁₋₅-alkylcarbonyloxy, C₁₋₅-alkyloxycarbonyloxy,     carboxy-C₁₋₃-alkyloxy, C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy,     C₁₋₈-alkyloxycarbonylamino, mercapto, C₁₋₃-alkylsulphanyl,     C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,     C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphanyl,     C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphinyl,     C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphonyl, carboxy,     C₁₋₃-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl,     benzyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,     di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₆-cycloalkyleneiminocarbonyl,     aminosulphonyl, C₁₋₃-alkylaminosulphonyl,     di-(C₁₋₃-alkyl)-aminosulphonyl, C₃₋₆-cycloalkyleneiminosulphonyl,     amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,     C₁₋₅-alkylcarbonylamino, C₁₋₃-alkyl-sulphonylamino,     N—(C₁₋₃-alkylsulphonyl)-C₁₋₃-alkylamino,     C₃₋₆-cycloalkylcarbonyl-amino, aminocarbonylamino,     C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)-amino-carbonylamino, a     4- to 7-membered cycloalkyleneiminocarbonylamino,     benzyl-oxycarbonylamino, phenylcarbonylamino or guanidino group,

-   a carboxy, aminocarbonyl, C₁₋₄-alkylaminocarbonyl,     C₃₋₆-cycloalkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,     C₁₋₄-alkoxycarbonyl, C₄₋₆-cycloalkyleneiminocarbonyl group,

-   a phenyl or heteroaryl, phenylcarbonyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl     or heteroaryl -C₁₋₃-alkyl group which is optionally mono- or     polysubstituted in the phenyl or heteroaryl moiety by fluorine,     chlorine or bromine atoms, C₁₋₃-alkyl, amino, C₁₋₃-alkylamino,     di-(C₁₋₃-alkyl)-amino, hydroxy, C₁₋₄-alkyloxy, mono-, di- or     trifluoromethoxy, benzyloxy, carboxy-C₁₋₃-alkyloxy,     C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,     C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyloxy,     di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy, a 4- to 7-membered     cycloalkyleneiminocarbonyl-C₁₋₃-alkoxy, carboxy,     C₁₋₃-alkyloxycarbonyl or C₁₋₃-alkyloxycarbonylamino group,

-   a 3- to 7-membered cycloalkyl, cycloalkyleneimino,     cycloalkyl-C₁₋₃-alkyl or cycloalkyleneimino-C₁₋₃-alkyl group wherein     in the cyclic moiety a methylene group may be replaced by an —NH—     group optionally substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl     group or by an oxygen atom and wherein additionally a methylene     group adjacent to the —NH—, —N(C₁₋₃-alkylcarbonyl)- or     —N(C₁₋₃-alkyl)-group may be replaced in each case by a carbonyl or     sulphonyl group, with the proviso that a cycloalkyleneimino group as     hereinbefore defined wherein two nitrogen atoms are separated from     one another by precisely one —CH₂— group is excluded,

-   R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group or

-   R³ and R⁴ together with the carbon atom to which they are bound,     denote a C₃₋₇-cycloalkyl group, while     -   one of the methylene groups of the C₃₋₇-cycloalkyl group may be         replaced by an imino, C₁₋₃-alkylimino, acylimino or         sulphonylimino group,

-   R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group,

B denotes a group of formula

wherein

-   -   n denotes the number 1 or 2,     -   R⁷ denotes a hydrogen atom or a C₁₋₃-alkyl, hydroxy,         C₁₋₅-alkyloxycarbonyl, carboxy-C₁₋₃-alkyl,         C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyl, amino or C₁₋₃-alkylamino group         and     -   R⁸ independently of one another denote a hydrogen, fluorine,         chlorine, bromine or iodine atom, a C₁₋₃-alkyl group wherein the         hydrogen atoms may be wholly or partly replaced by fluorine         atoms, a C₂₋₃-alkenyl or C₂₋₃-alkynyl, a hydroxy, C₁₋₃-alkoxy,         trifluoromethoxy, amino, nitro or nitrile group,

-   while, unless otherwise stated, by the term “heteroaryl group”     mentioned hereinbefore in the definitions is meant a monocyclic 5-     or 6-membered heteroaryl group, while     -   the 6-membered heteroaryl group contains one, two or three         nitrogen atoms and     -   the 5-membered heteroaryl group contains an imino group         optionally substituted by a C₁₋₃-alkyl, phenyl or         phenyl-C₁₋₃-alkyl group, an oxygen or sulphur atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl, phenyl,         amino-C₂₋₃-alkyl, C₁₋₃-alkylamino-C₂₋₃-alkyl,         di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl, a 4- to 7-membered         cycloalkyleneimino-C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group or an         oxygen or sulphur atom and additionally a nitrogen atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl or         phenyl-C₁₋₃-alkyl group and two or three nitrogen atoms,

-   and moreover a phenyl ring optionally substituted by a fluorine,     chlorine or bromine atom, a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy     group, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or     C₃₋₆-cycloalkyleneimino group may be fused to the above-mentioned     monocyclic heteroaryl groups via two adjacent carbon atoms     -   and the bond is effected via a nitrogen atom or a carbon atom of         the heterocyclic moiety or a fused-on phenyl ring,

-   while the alkyl and alkoxy groups contained in the above-mentioned     definitions which have more than two carbon atoms may, unless     otherwise stated, be straight-chain or branched and the alkyl groups     in the previously mentioned dialkylated groups, for example the     dialkylamino groups, may be identical or different,

-   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms,

-   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

Examples of monocyclic heteroaryl groups are the pyridyl, N-oxy-pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, [1,2,3]triazinyl, [1,3,5]triazinyl, [1,2,4]triazinyl, pyrrolyl, imidazolyl, [1,2,4]triazolyl, [1,2,3]triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, [1,2,3]oxadiazolyl, [1,2,4]oxadiazolyl, furazanyl, thiophenyl, thiazolyl, isothiazolyl, [1,2,3]thiadiazolyl, [1,2,4]thiadiazolyl or [1,2,5]thiadiazolyl group.

Examples of bicyclic heteroaryl groups are the benzimidazolyl, benzofuranyl, benzo[c]furanyl, benzothiophenyl, benzo[c]thiophenyl, benzothiazolyl, benzo[c]-isothiazolyl, benzo[d]isothiazolyl, benzoxazolyl, benzo[c]isoxazolyl, benzo[d]-isoxazolyl, benzo[1,2,5]oxadiazolyl, benzo[1,2,5]thiadiazolyl, benzo[1,2,3]thia-diazolyl, benzo[d][1,2,3]triazinyl, benzo[1,2,4]triazinyl, benzotriazolyl, cinnolinyl, quinolinyl, N-oxy-quinolinyl, isoquinolinyl, quinazolinyl, N-oxy-quinazolinyl, quinoxalinyl, phthalazinyl, indolyl, isoindolyl or 1-oxa-2,3-diaza-indenyl group.

Examples of the C₁₋₈-alkyl groups mentioned hereinbefore in the definitions are the methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl group.

Examples of the C₁₋₈-alkyloxy groups mentioned hereinbefore in the definitions are the methyloxy, ethyloxy, 1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, neo-pentyloxy, 1-hexyloxy, 2-hexyloxy, 3-hexyloxy, 1-heptyloxy, 2-heptyloxy, 3-heptyloxy, 4-heptyloxy, 1-octyloxy, 2-octyloxy, 3-octyloxy or 4-octyloxy group.

By a group which can be converted in vivo into a carboxy group is meant for example a carboxy group esterified with an alcohol wherein the alcohol moiety is preferably a C₁₋₈-alkanol, a phenyl-C₁₋₃-alkanol, a C₃₋₉-cycloalkanol, a C₅₋₇-cycloalkenol, a C₃₋₅-alkenol, a phenyl-C₃₋₅-alkenol, a C₃₋₅-alkynol or phenyl-C₃₋₅-alkynol with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C₃₋₈-cycloalkyl-C₁₋₃-alkanol or an alcohol of formula R⁹—CO—O—(R¹⁰CR¹¹)—OH, wherein

-   -   R⁹ denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or         phenyl-C₁₋₃-alkyl group,     -   R¹⁰ denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or         phenyl group and         R¹¹ denotes a hydrogen atom or a C₁₋₃-alkyl group.

Preferred groups which may be cleaved from a carboxy group in vivo include a C₁₋₆-alkoxy group such as the methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyl-oxy, n-pentyloxy, n-hexyloxy or cyclohexyloxy group or a phenyl-C₁₋₃-alkoxy group such as the benzyloxy group.

Those compounds of general formula I wherein R³ contains a group which may be converted in vivo into a carboxy group are prodrugs for those compounds of general formula I wherein R³ contains a carboxy group.

A 2nd embodiment of the present invention comprises those compounds of general formula I wherein

A denotes a group of general formula

wherein m denotes the number 1 or 2,

-   R^(6a) independently of one another denote a hydrogen or fluorine     atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino,     di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,     di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group and -   R^(6b) independently of one another may be a hydrogen atom, a     C₁₋₄-alkyl, C₁₋₄-alkyl-carbonyl, C₁₋₄-alkoxycarbonyl or     C₁₋₃-alkylsulphonyl group, with the proviso that     -   in the above-mentioned substituted 5- to 7-membered groups A the         heteroatoms optionally introduced as substituents are not         separated from another heteroatom by precisely one carbon atom,         or

a group of general formula

wherein

-   -   m denotes the number 1 or 2,     -   X¹ denotes a methylene, —NR^(6b)—, carbonyl or sulphonyl group,     -   X² denotes an oxygen atom or a —NR^(6b) group,     -   X³ denotes a methylene, carbonyl or sulphonyl group,     -   X⁴ denotes an oxygen or sulphur atom, a —NR^(6b) or carbonyl         group,     -   X⁵ denotes a carbonyl or sulphonyl group,     -   X⁸ denotes a carbonyl group,     -   X⁹ denotes a carbonyl group,     -   R^(6a) independently of one another denote a hydrogen or         fluorine atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino,         di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,         di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group         and     -   R^(6b) independently of one another may be a hydrogen atom, a         C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or         C₁₋₃-alkylsulphonyl group, with the proviso that         -   in the above-mentioned substituted 5- to 7-membered cyclic             groups A the heteroatoms introduced as substituents are not             separated from another heteroatom by precisely one carbon             atom,

-   R¹ denotes a hydrogen, fluorine, chlorine or bromine atom, a     C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partly     replaced by fluorine atoms, a C₂₋₃-alkenyl, C₂₋₃-alkynyl, nitro,     amino, C₁₋₃-alkoxy, a mono-, di- or trifluoromethoxy group,

-   R² denotes a hydrogen, fluorine, chlorine or bromine atom or a     C₁₋₃-alkyl group,

-   R³ denotes a C₂₋₃-alkenyl or C₂₋₃-alkynyl group or a straight-chain     or branched C₁₋₈-alkyl group wherein the hydrogen atoms may be     wholly or partly replaced by fluorine atoms, and which is optionally     substituted by a nitrile, hydroxy, a C₁₋₅-alkyloxy group wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms,     an allyloxy, propargyloxy, benzyloxy, C₁₋₅-alkylcarbonyloxy,     C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy,     C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy, C₁₋₈-alkyloxycarbonylamino,     mercapto, C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphinyl,     C₁₋₃-alkylsulphonyl, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphanyl,     C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphinyl,     C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphonyl, carboxy,     C₁₋₃-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl,     benzyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,     di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₆-cycloalkyleneiminocarbonyl,     aminosulphonyl, C₁₋₃-alkylaminosulphonyl,     di-(C₁₋₃-alkyl)-aminosulphonyl, C₃₋₆-cycloalkyleneiminosulphonyl,     amino, C₁₋₃-alkyl-amino, di-(C₁₋₃-alkyl)-amino,     C₁₋₅-alkylcarbonylamino, C₁₋₃-alkylsulphonylamino,     N—(C₁₋₃-alkylsulphonyl)-C₁₋₃-alkylamino,     C₃₋₆-cycloalkylcarbonylamino, aminocarbonylamino,     C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)-aminocarbonylamino, a     4- to 7-membered cycloalkyleneiminocarbonylamino,     benzyloxycarbonylamino, phenylcarbonylamino or guanidino group,

-   a carboxy, aminocarbonyl, C₁₋₄-alkylaminocarbonyl,     C₃₋₆-cycloalkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,     C₁₋₄-alkoxycarbonyl, C₄₋₆-cycloalkyleneiminocarbonyl group,

-   a phenyl or heteroaryl, phenylcarbonyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl     or heteroaryl-C₁₋₃-alkyl group which is optionally mono- or     polysubstituted in the phenyl or heteroaryl moiety by fluorine,     chlorine or bromine atoms, C₁₋₃-alkyl, amino, C₁₋₃-alkylamino,     di-(C₁₋₃-alkyl)-amino, hydroxy, C₁₋₄-alkyloxy, mono-, di- or     trifluoromethoxy, benzyloxy, carboxy-C₁₋₃-alkyloxy,     C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy,     C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyloxy,     di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy, a 4- to 7-membered     cycloalkyleneiminocarbonyl-C₁₋₃-alkoxy, carboxy,     C₁₋₃-alkyloxycarbonyl or C₁₋₃-alkyloxycarbonylamino group,

-   a 3- to 7-membered cycloalkyl, cycloalkyleneimino,     cycloalkyl-C₁₋₃-alkyl or cycloalkyleneimino-C₁₋₃-alkyl group wherein     in the cyclic moiety a methylene group may be replaced by a —NH—     group optionally substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl     group or by an oxygen atom and wherein additionally a methylene     group adjacent to the —NH—, —N(C₁₋₃-alkylcarbonyl)- or     —N(C₁₋₃-alkyl)-group may be replaced in each case by a carbonyl or     sulphonyl group, with the proviso that a cycloalkyleneimino group as     hereinbefore defined wherein two nitrogen atoms are separated from     one another by precisely one —CH₂— group is excluded,

-   R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group,

-   R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group,

B denotes a group of formula

wherein

-   -   n denotes the number 1 or 2,     -   R⁷ denotes a hydrogen atom, a C₁₋₃-alkyl, hydroxy,         C₁₋₅-alkyloxycarbonyl, carboxy-C₁₋₃-alkyl,         C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyl, amino or C₁₋₃-alkylamino group         and     -   R⁸ independently of one another denote a hydrogen, fluorine,         chlorine, bromine or iodine atom, a C₁₋₃-alkyl group wherein the         hydrogen atoms may be wholly or partly replaced by fluorine         atoms, a C₂₋₃-alkenyl or C₂₋₃-alkynyl, a hydroxy, C₁₋₃-alkoxy,         trifluoromethoxy, amino, nitro or nitrile group,

-   while, unless otherwise stated, by the term “heteroaryl group”     mentioned hereinbefore in the definitions is meant a monocyclic 5-     or 6-membered heteroaryl group, while     -   the 6-membered heteroaryl group contains one, two or three         nitrogen atoms and     -   the 5-membered heteroaryl group contains an imino group         optionally substituted by a C₁₋₃-alkyl, phenyl or         phenyl-C₁₋₃-alkyl group, an oxygen or sulphur atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl, phenyl,         amino-C₂₋₃-alkyl, C₁₋₃-alkylamino-C₂₋₃-alkyl,         di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl, a 4- to 7-membered         cycloalkyleneimino-C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group or an         oxygen or sulphur atom and additionally a nitrogen atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl or         phenyl-C₁₋₃-alkyl group and two or three nitrogen atoms,     -   and moreover a phenyl ring optionally substituted by a fluorine,         chlorine or bromine atom, a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy         group, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or         C₃₋₆-cycloalkyleneimino group may be fused to the         above-mentioned monocyclic heteroaryl groups via two adjacent         carbon atoms     -   and the bond is effected via a nitrogen atom or a carbon atom of         the heterocyclic moiety or a fused-on phenyl ring,

-   while the alkyl and alkoxy groups contained in the above-mentioned     definitions which have more than two carbon atoms may, unless     otherwise stated, be straight-chain or branched and the alkyl groups     in the previously mentioned dialkylated groups, for example the     dialkylamino groups, may be identical or different,

-   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms,

-   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

A 3rd embodiment of the present invention comprises those compounds of general formula I, wherein

A denotes a group of general formula

wherein m denotes the number 1 or 2,

-   R^(6a) independently of one another denote a hydrogen or fluorine     atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino,     di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,     di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group and -   R^(6b) independently of one another may be a hydrogen atom, a     C₁₋₄-alkyl, C₁₋₄-alkyl-carbonyl, C₁₋₄-alkoxycarbonyl or     C₁₋₃-alkylsulphonyl group, with the proviso that     -   in the above-mentioned substituted 5- to 7-membered groups A the         heteroatoms optionally introduced as substituents are not         separated from another heteroatom by precisely one carbon atom,         or

a group of general formula

wherein

-   -   m denotes the number 1 or 2,     -   X¹ denotes a methylene, —NR^(6b)—, carbonyl or sulphonyl group,     -   X² denotes an oxygen atom or a —NR^(6b) group,     -   X³ denotes a methylene, carbonyl or sulphonyl group,     -   X⁴ denotes an oxygen or sulphur atom or a —NR^(6b) group,     -   X⁵ denotes a carbonyl or sulphonyl group,     -   R^(6a) independently of one another denote a hydrogen or         fluorine atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino,         di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,         di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group         and     -   R^(6b) independently of one another may be a hydrogen atom, a         C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or         C₁₋₃-alkylsulphonyl group, with the proviso that         -   in the above-mentioned substituted 5- to 7-membered cyclic             groups A the heteroatoms introduced as substituents are not             separated from another heteroatom by precisely one carbon             atom,

-   R¹ denotes a fluorine, chlorine or bromine atom, a C₁₋₃-alkyl group     wherein the hydrogen atoms may be wholly or partly replaced by     fluorine atoms, a nitro, C₁₋₃-alkoxy, a mono-, di- or     trifluoromethoxy group,

-   R² denotes a hydrogen atom,

-   R³ denotes a straight-chain or branched C₁₋₆-alkyl group wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms,     and which is optionally substituted by a nitrile, hydroxy,     benzyloxy, a C₁₋₅-alkyloxy group wherein the hydrogen atoms may be     wholly or partly replaced by fluorine atoms, an allyloxy,     C₁₋₅-alkylcarbonyloxy, C₁₋₅-alkyloxycarbonyloxy,     carboxy-C₁₋₃-alkyloxy, C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy,     C₁₋₈-alkyloxycarbonylamino, C₁₋₃-alkylsulphanyl,     C₁₋₃-alkylsulphonyl, carboxy, C₁₋₃-alkyloxycarbonyl,     C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,     C₃₋₆-cycloalkyleneiminocarbonyl, aminocarbonylamino,     C₁₋₃-alkylaminocarbonylamino or di-(C₁₋₃-alkyl)-aminocarbonylamino     group, an aminocarbonyl, C₁₋₄-alkylaminocarbonyl,     C₃₋₆-cycloalkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group,

-   a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl     group which is optionally mono- or polysubstituted in the phenyl or     heteroaryl moiety by fluorine, chlorine or bromine atoms,     C₁₋₃-alkyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, hydroxy,     C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, or     C₁₋₃-alkyloxycarbonyl group,

-   a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a     methylene group may be replaced by a —NH— group optionally     substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group, or an     oxygen atom,

-   R⁴ denotes a hydrogen atom,

-   R⁵ denotes a hydrogen atom,

B denotes a group of formula

wherein

-   -   n denotes the number 1,     -   R⁷ denotes a hydrogen atom and     -   R⁸ denotes a hydrogen, fluorine, chlorine, bromine or iodine         atom, a methyl, C₂₋₃-alkynyl, or methoxy group, wherein the         hydrogen atoms may be wholly or partly replaced by fluorine         atoms,

-   while, unless otherwise stated, by the term “heteroaryl group”     mentioned hereinbefore in the definitions is meant a monocyclic 5-     or 6-membered heteroaryl group, while     -   the 6-membered heteroaryl group contains one, two or three         nitrogen atoms and     -   the 5-membered heteroaryl group contains an imino group         optionally substituted by a C₁₋₃-alkyl group, an oxygen or         sulphur atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group or         an oxygen or sulphur atom and additionally a nitrogen atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group and         two or three nitrogen atoms,     -   and the bond is effected via a nitrogen atom or via a carbon         atom,

-   while the alkyl and alkoxy groups contained in the above-mentioned     definitions which have more than two carbon atoms may, unless     otherwise stated, be straight-chain or branched and the alkyl groups     in the previously mentioned dialkylated groups, for example the     dialkylamino groups, may be identical or different,

-   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms,

-   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

A 4th embodiment of the present invention comprises those compounds of general formula I wherein

-   A, R¹, R², R⁴, R⁵ and B are defined as described under the 3rd     embodiment and -   R³ denotes a straight-chain or branched C₁₋₆-alkyl group wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms,     and which is optionally substituted by a nitrile, hydroxy,     benzyloxy, a C₁₋₅-alkyloxy group wherein the hydrogen atoms may be     wholly or partly replaced by fluorine atoms, an allyloxy,     C₁₋₅-alkylcarbonyloxy, C₁₋₅-alkyloxycarbonyloxy,     carboxy-C₁₋₃-alkyloxy, C₁₋₅-alkyl-oxycarbonyl-C₁₋₃-alkyloxy,     C₁₋₈-alkyloxycarbonylamino, C₁₋₃-alkylsulphanyl,     C₁₋₃-alkylsulphonyl, carboxy, C₁₋₃-alkyloxycarbonyl,     C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,     C₃₋₆-cycloalkyleneiminocarbonyl, aminocarbonylamino,     C₁₋₃-alkylaminocarbonylamino or di-(C₁₋₃-alkyl)-aminocarbonylamino     group, an aminocarbonyl, C₁₋₄-alkylaminocarbonyl,     C₃₋₆-cycloalkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group, -   while the alkyl and alkoxy groups contained in the above-mentioned     definitions which have more than two carbon atoms may, unless     otherwise stated, be straight-chain or branched and the alkyl groups     in the previously mentioned dialkylated groups, for example the     dialkylamino groups, may be identical or different, -   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

A 5th embodiment of the present invention comprises those compounds of general formula I wherein

-   A, R¹, R², R⁴, R⁵ and B are defined as described under the 3rd     embodiment and -   R³ denotes a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl or     heteroaryl-C₁₋₃-alkyl group which is optionally mono- or     polysubstituted in the phenyl or heteroaryl moiety by fluorine,     chlorine or bromine atoms, C₁₋₃-alkyl, amino, C₁₋₃-alkylamino,     di-(C₁₋₃-alkyl)-amino, hydroxy, C₁₋₄-alkyloxy, mono-, di- or     trifluoromethoxy, carboxy, or C₁₋₃-alkyloxycarbonyl group, -   a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a     methylene group may be replaced by a —NH— group optionally     substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group, or by an     oxygen atom, -   while, unless otherwise stated, by the term “heteroaryl group”     mentioned hereinbefore in the definitions is meant a monocyclic 5-     or 6-membered heteroaryl group, while     -   the 6-membered heteroaryl group contains one, two or three         nitrogen atoms and     -   the 5-membered heteroaryl group contains an imino group         optionally substituted by a C₁₋₃-alkyl group, an oxygen or         sulphur atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group or         an oxygen or sulphur atom and additionally a nitrogen atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group and         two or three nitrogen atoms,     -   and the bond is effected via a nitrogen atom or via a carbon         atom, -   while the alkyl groups contained in the foregoing definitions which     have more than two carbon atoms may, unless otherwise stated, be     straight-chain or branched and the alkyl groups in the previously     mentioned dialkylated groups, for example the dialkylamino groups,     may be identical or different, -   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

A 6th embodiment of the present invention comprises those compounds of general formula I, wherein

A denotes a group of general formula

wherein m denotes the number 1 or 2,

-   R^(6a) independently of one another denote a hydrogen or fluorine     atom or a C₁₋₃-alkyl group and -   R^(6b) may be a hydrogen atom or a C₁₋₃-alkyl group, with the     proviso that     -   in the above-mentioned substituted 5- to 7-membered groups A the         heteroatoms optionally introduced as substituents are not         separated from another heteroatom by precisely one carbon atom,         or

a group of general formula

wherein

-   -   m denotes the number 1 or 2,     -   X¹ denotes a methylene, —NR^(6b)—, carbonyl or sulphonyl group,     -   X² denotes an oxygen atom or a —NR^(6b) group,     -   X³ denotes a methylene, carbonyl or sulphonyl group,     -   X⁴ an oxygen or sulphur atom or a —NR^(6b) group,     -   X⁵ denotes a carbonyl or sulphonyl group,     -   R^(6a) independently of one another denote a hydrogen or         fluorine atom or a C₁₋₃-alkyl group and     -   R^(6b) independently of one another may be a hydrogen atom or a         C₁₋₃-alkyl group, with the proviso that         -   in the above-mentioned substituted 5- to 7-membered cyclic             groups A the heteroatoms introduced as substituents are not             separated from another heteroatom by precisely one carbon             atom,

-   R¹ denotes a chlorine or bromine atom, a methyl or methoxy group,     wherein the hydrogen atoms may be wholly or partly replaced by     fluorine atoms, or a nitro group,

-   R² denotes a hydrogen atom,

-   R³ denotes a straight-chain or branched C₁₋₄-alkyl group wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms,     and which is optionally substituted by a hydroxy, a C₁₋₄-alkyloxy     group wherein the hydrogen atoms may be wholly or partly replaced by     fluorine atoms, a C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy     or C₁₋₃-alkyloxycarbonyl group,

-   a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl     group which is optionally mono- or polysubstituted in the phenyl or     heteroaryl moiety by fluorine, chlorine or bromine atoms,     C₁₋₃-alkyl, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, carboxy,     or C₁₋₃-alkyloxycarbonyl group,

-   R⁴ denotes a hydrogen atom,

-   R⁵ denotes a hydrogen atom and

-   B denotes a group of formula

wherein

-   n denotes the number 1, -   R⁷ denotes a hydrogen atom and -   R⁸ denotes a chlorine or bromine atom or the ethynyl group, -   while, unless otherwise stated, by the term “heteroaryl group”     mentioned hereinbefore in the definitions is meant a monocyclic 5-     or 6-membered heteroaryl group, while     -   the 6-membered heteroaryl group contains one, two or three         nitrogen atoms and     -   the 5-membered heteroaryl group contains an imino group         optionally substituted by a C₁₋₃-alkyl group, an oxygen or         sulphur atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group or         an oxygen or sulphur atom and additionally a nitrogen atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group and         two or three nitrogen atoms,     -   and the bond is effected via a nitrogen atom or via a carbon         atom, -   while the alkyl groups contained in the foregoing definitions which     have more than two carbon atoms may, unless otherwise stated, be     straight-chain or branched and the alkyl groups in the previously     mentioned dialkylated groups, for example the dialkylamino groups,     may be identical or different, -   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

A 7th embodiment of the present invention comprises those compounds of general formula I, wherein

-   A, R¹, R², R⁴, R⁵ and B are defined as described under the 6th     embodiment and -   R³ denotes a straight-chain or branched C₁₋₄-alkyl group wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms,     and which is optionally substituted by a hydroxy, a C₁₋₄-alkyloxy     group wherein the hydrogen atoms may be wholly or partly replaced by     fluorine atoms, a C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy     or C₁₋₃-alkyloxycarbonyl group, -   while the alkyl and alkoxy groups contained in the above-mentioned     definitions which have more than two carbon atoms may, unless     otherwise stated, be straight-chain or branched and the alkyl groups     in the previously mentioned dialkylated groups, for example the     dialkylamino groups, may be identical or different, -   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

An 8th embodiment of the present invention comprises those compounds of general formula I, wherein

-   A, R¹, R², R⁴, R⁵ and B are defined as described under the 6th     embodiment and -   R³ denotes a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl or     heteroaryl-C₁₋₃-alkyl group which is optionally mono- or     polysubstituted in the phenyl or heteroaryl moiety by fluorine,     chlorine or bromine atoms, C₁₋₃-alkyl, C₁₋₄-alkyloxy, mono-, di- or     trifluoromethoxy, carboxy, or C₁₋₃-alkyloxycarbonyl group, -   a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a     methylene group may be replaced by a —NH— group optionally     substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group, or by an     oxygen atom, -   while, unless otherwise stated, by the term “heteroaryl group”     mentioned hereinbefore in the definitions is meant a monocyclic 5-     or 6-membered heteroaryl group, while     -   the 6-membered heteroaryl group contains one, two or three         nitrogen atoms and     -   the 5-membered heteroaryl group contains an imino group         optionally substituted by a C₁₋₃-alkyl group, an oxygen or         sulphur atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group or         an oxygen or sulphur atom and additionally a nitrogen atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group and         two or three nitrogen atoms,     -   and the bond is effected via a nitrogen atom or via a carbon         atom, -   while the alkyl groups contained in the foregoing definitions which     have more than two carbon atoms may, unless otherwise stated, be     straight-chain or branched and the alkyl groups in the previously     mentioned dialkylated groups, for example the dialkylamino groups,     may be identical or different, -   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms, the tautomers, the enantiomers, the diastereomers,     the mixtures thereof and the salts thereof.

A 9th embodiment of the present invention comprises those compounds of general formula I, wherein

A denotes a group of formula

wherein

-   -   m denotes the number 1 or 2,     -   R^(6a) independently of one another denote a hydrogen or         fluorine atom or a C₁₋₃-alkyl group, with the proviso that         -   in the above-mentioned substituted 5- to 7-membered cyclic             groups A the fluorine atoms introduced as substituents are             not separated from another heteroatom by precisely one             carbon atom,

-   R¹ denotes a chlorine or bromine atom, a methyl or methoxy group,     wherein the hydrogen atoms may be wholly or partly replaced by     fluorine atoms, or a nitro group,

-   R² denotes a hydrogen atom,

-   R³ denotes a straight-chain or branched C₁₋₄-alkyl group wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms,     and which is optionally substituted by a hydroxy, a C₁₋₄-alkyloxy     group wherein the hydrogen atoms may be wholly or partly replaced by     fluorine atoms, a C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy     or C₁₋₃-alkyloxycarbonyl group,

-   a furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl,     isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,     pyridinyl-C₁₋₂-alkyl or imidazolyl-C₁₋₂-alkyl group which may     optionally be substituted in the heteroaryl moiety by one or two     C₁₋₃-alkyl groups, C₁₋₃-alkyloxy groups, carboxy or     C₁₋₃-alkyloxycarbonyl groups, and

-   R⁴ denotes a hydrogen atom,

-   R⁵ denotes a hydrogen atom and

-   B denotes a group of formula

wherein

-   n denotes the number 1, -   R⁷ denotes a hydrogen atom and -   R⁸ denotes a chlorine or bromine atom or an ethynyl group, -   while, unless otherwise stated, by the term “heteroaryl group”     mentioned hereinbefore in the definitions is meant a monocyclic 5-     or 6-membered heteroaryl group, while     -   the 6-membered heteroaryl group contains one, two or three         nitrogen atoms and     -   the 5-membered heteroaryl group contains an imino group         optionally substituted by a C₁₋₃-alkyl group, an oxygen or         sulphur atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group or         an oxygen or sulphur atom and additionally a nitrogen atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group and         two or three nitrogen atoms,     -   and the bond is effected via a nitrogen atom or via a carbon         atom, -   while the alkyl groups contained in the foregoing definitions which     have more than two carbon atoms may, unless otherwise stated, be     straight-chain or branched and the alkyl groups in the previously     mentioned dialkylated groups, for example the dialkylamino groups,     may be identical or different, -   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

A 10th embodiment of the present invention comprises those compounds of general formula I, wherein

-   A, R¹, R², R⁴, R⁵ and B are defined as described under the 9th     embodiment and -   R³ denotes a straight-chain or branched C₁₋₄-alkyl group wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms,     and which is optionally substituted by a hydroxy, a C₁₋₄-alkyloxy     group wherein the hydrogen atoms may be wholly or partly replaced by     fluorine atoms, a C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy     or C₁₋₃-alkyloxycarbonyl group, -   while the alkyl and alkoxy groups contained in the above-mentioned     definitions which have more than two carbon atoms may, unless     otherwise stated, be straight-chain or branched and the alkyl groups     in the previously mentioned dialkylated groups, for example the     dialkylamino groups, may be identical or different, -   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

An 11th embodiment of the present invention comprises those compounds of general formula I wherein

-   A, R¹, R², R⁴, R⁵ and B are defined as described under the 9th     embodiment and denote a furanyl, thiophenyl, pyrrolyl, pyrazolyl,     imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl,     pyrazinyl, pyridinyl-C₁₋₂-alkyl or imidazolyl-C₁₋₂-alkyl group which     may optionally be substituted in the heteroaryl moiety by one or two     C₁₋₃-alkyl groups, wherein the hydrogen atoms may be wholly or     partly replaced by fluorine atoms, C₁₋₃-alkyloxy groups, wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms,     carboxy or C₁₋₃-alkyloxycarbonyl groups, and -   unless otherwise stated, by the term “heteroaryl group” mentioned     hereinbefore in the definitions is meant a monocyclic 5- or     6-membered heteroaryl group, while     -   the 6-membered heteroaryl group contains one, two or three         nitrogen atoms and     -   the 5-membered heteroaryl group contains an imino group         optionally substituted by a C₁₋₃-alkyl group, an oxygen or         sulphur atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group or         an oxygen or sulphur atom and additionally a nitrogen atom or     -   an imino group optionally substituted by a C₁₋₃-alkyl group and         two or three nitrogen atoms,     -   and the bond is effected via a nitrogen atom or via a carbon         atom, -   while the alkyl groups contained in the foregoing definitions which     have more than two carbon atoms may, unless otherwise stated, be     straight-chain or branched and the alkyl groups in the previously     mentioned dialkylated groups, for example the dialkylamino groups,     may be identical or different, -   and the hydrogen atoms of the methyl or ethyl groups contained in     the foregoing definitions may be wholly or partly replaced by     fluorine atoms, -   the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof.

A 12th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7 and 8, wherein the group X¹ denotes a methylene group.

A 13th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7 and 8, wherein the group X¹ denotes a carbonyl group.

A 14th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 12 and 13, wherein the group X³ denotes a methylene group.

A 15th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 12 and 13 wherein the group X³ denotes a carbonyl group.

A 16th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 12, 13, 14 and 15, wherein the group X⁴ denotes an oxygen atom.

A 17th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16, wherein the group B denotes the group

An 18th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16, wherein the group B denotes the group

A 19th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16, wherein the group B denotes the group

A 20th embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19, wherein the group R⁸ denotes a chlorine atom.

A 21st embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19, wherein the group R⁸ denotes a bromine atom.

A 22nd embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19, wherein the group R⁸ denotes an ethynyl group.

A 23rd embodiment of the present invention comprises those compounds of general formula I corresponding to the embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22, which correspond to general formula Ia

The following preferred compounds of general formula I will now be mentioned by way of example:

-   (1)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]diazepan-1-yl)-benzamide, -   (2)     4-(4-N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide, -   (3)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide, -   (4)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl)-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide, -   (5)     4-(4-N-acetyl-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide, -   (6)     4-(azepan-2-on-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide, -   (7)     4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-benzamide, -   (8)     4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-benzamide, -   (9)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrrolidin-2-on-1-yl)-benzamide, -   (10)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide, -   (11)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide, -   (12)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzamide, -   (13)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(2-methyl-pyrrolidin-1-yl)-benzamide, -   (14)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-chloro-4-(morpholin-1-yl)-benzamide, -   (15)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3,5-difluoro-4-(morpholin-1-yl)-benzamide, -   (16)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-4-(morpholin-1-yl)-benzamide, -   (17)     4-(azepan-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide, -   (18)     4-(azepan-1-yl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-benzamide, -   (19)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-1-yl)-benzamide, -   (20)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]oxazepan-4-yl)-benzamide, -   (21)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzamide, -   (22)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (23)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (24)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (25)     4-(azepan-2-on-1-yl)-3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-benzamide, -   (26)     4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-benzamide, -   (27)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-benzamide, -   (28)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (29)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-benzamide, -   (30)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide, -   (31)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-2-on-1-yl)-benzamide, -   (32)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide, -   (33)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(N-methyl-piperazin-1-yl)-3-trifluoromethyl-benzamide, -   (34)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphonyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (35)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(pyrrolidin-2-on-1-yl)-benzamide, -   (36)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-4-(pyrrolidin-2-on-1-yl)-benzamide, -   (37)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,5-dimethylpiperidin-1-yl)-benzamide, -   (38)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,4-didehydro-piperidin-1-yl)-benzamide, -   (39)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide -   (40)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl)-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide, -   (41)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide, -   (42)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide, -   (43)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide, -   (44)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide, -   (45)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-3-on-4-yl)-benzamide, -   (46)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide, -   (47)     N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (48)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzamide, -   (49)     N-[1-(5-chloro-1H-indol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (50)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-[2-(4-methyl-piperazin-1-yl-methyl)-piperidin-1-yl)-benzamide, -   (51)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(oxazolidin-2-on-3-yl)-benzamide, -   (52)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-benzamide, -   (53)     N-[(1R,2S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (54)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,5-dimethylpiperidin-1-yl)-benzamide, -   (55)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide, -   (56)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide, -   (57)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]-oxazinan-2-on-3-yl)-benzamide, -   (58)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]-oxazinan-2-on-3-yl)-benzamide, -   (59)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-3-trifluoromethyl-benzamide, -   (60)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-3-methyl-benzamide, -   (61)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(5,6-didehydro-azepan-2-on-1-yl)-benzamide, -   (62)     4-(azepan-2-on-1-yl)-N-[(1S)-1-(5-chloro-6-fluoro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide, -   (63)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,3-dioxo-thiomorpholin-4-yl)-3-methyl-benzamide, -   (64)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(1,1,3-trioxo-thiomorpholin-4-yl)-benzamide, -   (65)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide, -   (66)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperazin-2-on-1-yl)-benzamide, -   (67)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (68)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,3]oxazepan-2-on-3-yl)-3-trifluoromethyl-benzamide, -   (69)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methoxy-4-(piperidin-2-on-1-yl)-benzamide, -   (70)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methoxy-4-(piperidin-2-on-1-yl)-benzamide, -   (71)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide, -   (72)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide, -   (73)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-6-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide, -   (74)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-3-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide, -   (75)     N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (76)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (77)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (78)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-thiophen-3-yl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (79)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylsulphanyl-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (80)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide, -   (81)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide, -   (82)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamide, -   (83)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzamide, -   (84)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide, -   (85)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1-yl)-3-trifluoromethoxy-benzamide, -   (86)     3-bromo-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1-yl)-benzamide, -   (87)     3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide, -   (88)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(furan-2-yl)-methyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide, -   (89)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,2]oxazinan-2-yl)-benzamide, -   (90)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzamide, -   (91)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzamide, -   (92)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzamide, -   (93)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (94)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (95)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (96)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (97)     3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide, -   (98)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(7-oxo-[1,4]diazepan-1-yl)-benzamide, -   (99)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-1-(thiophen-2-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (100)     N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-3-methyl-benzamide, -   (101)     N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide, -   (102)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-(4S)-methyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (103)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4-dimethyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (104)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-(4R)-methyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (105)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4-(4R)-ethyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (106)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-(morpholin-3-on-4-yl)-benzamide, -   (107)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (108)     N-[1-(1S)-(5-chloro-1H-benzimidazol-2-yl)-2-cyano-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (109)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-pyridin-3-yl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (110)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-1-methyl-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (111)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(5-methyl-morpholin-3-on-4-yl)-benzamide, -   (112)     3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3-dimethylamino-pyrrolidin-1-yl)-benzamide, -   (113)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzamide, -   (114)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide, -   (115)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-chloro-4-([1,4]diazepan-1-yl)-benzamide, -   (116)     3-chloro-N-[1-(5-chloro-1H-indol-2-yl)-2-methoxy-ethyl]-4-([1,4]diazepan-1-yl)-benzamide, -   (117)     N-[1-(5-chloro-1H-indol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (118)     3-bromo-N-[1-(5-chloro-1H-indol-2-yl)-1-(furan-2-yl)-methyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide, -   (119)     N-[1-(5-bromo-1H-indol-2-yl)-1-(1-methyl-1H-pyrazol-3-yl)-methyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide, -   (120)     N-[1-(5-chloro-1H-indol-2-yl)-3-(methyl-sulphonyl)-propyl]-3-methyl-4-(tetrahydropyrimidin-2-on-1-yl)-benzamide, -   (121)     N-[1-(5-chloro-1H-indol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(5-methyl-pyrrolidin-2-on-1-yl)-benzamide, -   (122)     N-[1-(5-chloro-1H-indol-2-yl)-1-phenyl-methyl]-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide, -   (123)     4-(azepan-2-on-1-yl)-3-chloro-N-[1-(5-chloro-1H-indol-2-yl)-3-(1H-tetrazol-5-yl)-propyl]-benzamide, -   (124)     N-[1-(5-bromo-1H-indol-2-yl)-2-hydroxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide, -   (125)     3-chloro-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-4-(diazepan-1-yl)-benzamide, -   (126)     3-chloro-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-ethyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide, -   (127)     N-[(1S)-1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (128)     N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (129)     3-bromo-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-1-(1H-pyrazol-3-yl)-methyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide, -   (130)     N-[1-(7-bromo-imidazo[1,2a]pyridin-2-yl)-2-hydroxy-ethyl]-3-chloro-4-(4-methyl-piperazin-1-yl)-benzamide, -   (131)     N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (132)     N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-1-(furan-2-yl)-methyl]-4-(diazepan-1-yl)-3-trifluoromethyl-benzamide, -   (133)     N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-1-phenyl-methyl]-3-methyl-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-benzamide, -   (134)     3-chloro-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide, -   (135)     3-bromo-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-(methyl-sulphanyl)-propyl]-4-([1,4]oxazepan-3-on-4-yl)-benzamide, -   (136)     3-chloro-N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-hydroxy-ethyl]-4-(piperazin-2-on-1-yl)-benzamide, -   (137)     N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide, -   (138)     N-[1-(7-bromo-imidazo[1,2a]pyridin-2-yl)-3-methoxy-propyl]-3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzamide, -   (139)     N-[1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-2-trifluoromethoxy-ethyl]-3-methyl-4-([1,4]oxazepan-5-on-4-yl)-benzamide, -   (140)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (141)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-benzyloxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (142)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-benzyloxycarbonyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (143)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (144)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyrazin-2-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (145)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(oxazol-2-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (146)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-imidazol-4-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (147)     N[1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-difluoromethoxy-4-(morpholin-3-on-4-yl)-benzamide, -   (148)     N[1-(5-chloro-1H-benzimidazol-2-yl)-1-methyl-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (149)     N-[3-(5-chloro-1H-benzimidazol-2-yl)-tetrahydrofuran-3-yl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (150)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-(pyrrolidin-1-yl-carbonyl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (151)     N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (152)     N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (153)     N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide, -   (154)     3-bromo-N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide, -   (155)     N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-methyl-oxazolidin-2-on-3-yl)-benzamide, -   (156)     N-[1-(5-ethynyl-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,4]oxazepan-5-on-4-yl)-benzamide, -   (157)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(2-methyl-tetrahydropyridazin-1-yl)-benzamide,     the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof, while the compounds -   (1)     4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-benzamide, -   (2)     4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-benzamide, -   (3)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide, -   (4)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzamide, -   (5)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (6)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (7)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (8)     4-(azepan-2-on-1-yl)-3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-benzamide, -   (9)     4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-benzamide, -   (10)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide, -   (11)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide, -   (12)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide, -   (13)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide, -   (14)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide, -   (15)     N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (16)     N-[(1R,2S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (17)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide, -   (18)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide, -   (19)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]-oxazinan-2-on-3-yl)-benzamide, -   (20)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-3-trifluoromethyl-benzamide, -   (21)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-3-methyl-benzamide, -   (22)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (23)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,3]oxazepan-2-on-3-yl)-3-trifluoromethyl-benzamide, -   (24)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide, -   (25)     N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (26)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (27)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (28)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylsulphanyl-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (29)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide, -   (30)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide, -   (31)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzamide, -   (32)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide, -   (33)     3-bromo-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1-yl)-benzamide, -   (34)     3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide, -   (35)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(furan-2-yl)-methyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide, -   (36)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzamide, -   (37)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (38)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (39)     3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide, -   (40)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-1-(thiophen-2-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (41)     N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-3-methyl-benzamide, -   (42)     N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide, -   (43)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-(4S)-methyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (44)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4-dimethyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (45)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(4-(4R)-methyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (46)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4-(4R)-ethyl-2-oxo-oxazolidin-3-yl)-benzamide, -   (47)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-(morpholin-3-on-4-yl)-benzamide, -   (48)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (49)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-1-methyl-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (50)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(5-methyl-morpholin-3-on-4-yl)-benzamide, -   (51)     3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide, -   (52)     N-[1-(5-chloro-1H-benzimidazol-2-yl)-thiophen-3-yl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide, -   (53)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide -   (54)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl)-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide, -   (55)     N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide, -   (56)     N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide, -   (57)     N-[(1S)-1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide,     the tautomers, the enantiomers, the diastereomers, the mixtures     thereof and the salts thereof are particularly preferred.

Within the scope of the present application, where applicable, the “isomer”, “stereoisomer”, “diastereomer”, “enantiomer”, “chiral”, “racemate” or “racemic mixture” are defined as follows. Compounds of the same empirical formula which differ in the nature or arrangement of the bonding of their atoms or their connectivity or the spatial arrangement of the atoms in the molecule are known as “isomers”. Isomers which differ in the spatial arrangement of the atoms in the molecule and are not congruent, while having the same type of connectivity of their atoms, are known as “stereoisomers”. Stereoisomers which do not behave as image and mirror image to one another are known as “diastereomers”, and stereoisomers which behave as an image and mirror image to one another are known as “enantiomers”. Where an asymmetric centre or atom is present (also known as a stereocentre or chiral centre), for example in the case of a carbon atom substituted by four different substituents, the molecule has the attribute “chiral”, and a pair of enantiomers is possible. An enantiomer may be characterised by the absolute configuration of its stereocentre. The absolute configuration is described by means of the descriptors (R) and (S), which are determined by the application of the sequence rules according to Cahn, Ingold and Prelog, or by describing the rotation of the plane of polarised light as it interacts with the molecule, which is referred to as dextrorotatory or laevorotatory (i.e. accordingly with (+) or (−) as the descriptor). A chiral compound may occur both as an individual enantiomer or as a mixture of the corresponding enantiomers. A mixture which contains equal amounts of both enantiomers of a compound is known as a “racemate” or “racemic mixture”.

According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods:

(a) In order to prepare compounds of general formula

wherein R³ to R⁵ are as hereinbefore defined and Z¹ denotes the hydrogen atom or a protective group and B′ denotes a group of formula

wherein R⁷ and R⁸ are as hereinbefore defined:

cyclisation of a compound of general formula

optionally formed in the reaction mixture wherein

-   R³ to R⁵, R⁷ and R⁸ are as hereinbefore defined and Z¹ denotes the     hydrogen atom or a protective group, after which any protective     group used is cleaved.

The cyclisation is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide or tetralin, dimethylsulphoxide, methylene chloride, chloroform, tetrachloromethane, for example at temperatures between 0 and 250° C., but preferably between 20 and 100° C., optionally in the presence of a condensation agent such as phosphorus oxychloride, thionyl chloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, N,N′-dicyclohexylcarbodiimide or optionally also in the presence of a base such as potassium ethoxide or potassium-tert.-butoxide. The cyclisation may however also be carried out without a solvent and/or condensation agent.

Compounds of general formula (IV) may be obtained by acylation of compounds of general formula

wherein n, R⁷ and R⁸ are as hereinbefore defined, with compounds of general formula

wherein R³, R⁴ and R⁵ are as hereinbefore defined, Q denotes a halogen atom or a hydroxy, C₁₋₄-alkoxy or C₁₋₄-acyloxy group and Z¹ denotes a protective group, according to processes described in (e).

(b) In order to prepare a compound of general formula

wherein R³ to R⁵ are as hereinbefore defined, Z¹ denotes the hydrogen atom or a protective group, for example a C₁₋₅-alkyloxycarbonyl or benzyloxycarbonyl group, and B′ denotes a group of formula

wherein R⁷ and R⁸ are as hereinbefore defined:

-   -   i) transition metal-catalysed coupling and cyclisation of a         compound of general formula

-   -   wherein R³ denotes a phenyl or heteroaryl group and R⁴ denotes a         hydrogen atom and R⁵ is as hereinbefore defined, with a compound         of general formula

-   -   wherein R⁸ is as hereinbefore defined and Z¹ denotes a         protective group, for example an acetyl or methylsulphonyl         group, after which the protective group is cleaved.

The reaction sequence is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide, methylene chloride, chloroform or tetrachloromethane, for example at temperatures between 0 and 250° C., but preferably between 20 and 120° C., conveniently in the presence of transition metal catalysts such as bis-(triphenylphosphine)-palladium (II)-chloride, bis-(tricyclohexylphosphine)-palladium (II)-chloride, bis-(triethylphosphine)-palladium (II)-chloride or bis-(tri-o-tolylphosphine)-palladium (II)-chloride and optionally in the presence of a transition metal catalyst such as copper (I)-iodide, copper (I)-bromide or copper (I)-acetate and conveniently in the presence of a base

-   -   such as tetramethylguanidine, tetramethylethylenediamine or         N,N′-dimethylethylenediamine as well as optionally using an         inert gas atmosphere (for example nitrogen or argon).     -   ii) alkylation and subsequent reductive amination of a compound         of general formula

-   -   wherein R⁷ and R⁸ are as hereinbefore defined and Y denotes a         halogen atom, a C₁₋₄-alkoxy, C₁₋₄-alkoxyamino or a         N—C₁₋₄-alkoxy-N—C₁₋₄-alkyl-amino group, with a compound of         general formula         R⁴-M,  (IX)     -   wherein R⁴ is as hereinbefore defined and M denotes a metal such         as for example lithium, sodium or potassium, or a metal such as         for example magnesium, cadmium, copper or zinc, with a suitable         counter-ion, such as for example chloride, bromide or iodide, or         also a combination of two metals, such as for example magnesium         and copper, lithium and copper or zinc and copper, with suitable         counter-ions, such as for example cyanide, chloride, bromide or         iodide, as well as a grouping containing combinations thereof,         and subsequent reductive amination of the compounds thus         obtained.

The alkylation is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide, methylene chloride, chloroform, tetrachloromethane, diethyl ether, tert.-butyl-methyl-ether or tetrahydrofuran, for example, at temperatures between −100 and +100° C., but preferably between −100 and 30° C., with alkylating reagents such as Grignard reagents, organolithium reagents, Gilman or Knochel cuprates which may be produced by methods known from the literature, optionally using an inert gas atmosphere (nitrogen or argon). The subsequent reductive amination of the ketones formed after alkylation is carried out for example by reaction with ammonia, hydroxylamine, alkoxylamines, primary amines, hydroxyl-alkylamines or alkoxy-alkylamines followed by or accompanied by reduction, for example with hydride donors such as sodium borohydride, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride or diisobutylaluminium hydride in a solvent or mixture of solvents such as ethanol, isopropanol, benzene, toluene, pyridine, ethyleneglycol-dimethylether, diethyleneglycoldimethylether, N-alkylmorpholine, diethyl ether, tert.-butyl-methylether, tetrahydrofuran, hexane or cyclohexane or by hydrogenation optionally under pressure and conveniently in the presence of a catalyst such as Raney nickel, palladium, palladium charcoal, platinum or platinum oxide, in a solvent or mixture of solvents such as ethyl acetate, ethanol, isopropanol, benzene, toluene, pyridine, ethyleneglycol dimethylether, diethyleneglycol dimethylether, N—C₁₋₅-alkylmorpholine, diethyl ether, tert.-butyl-methylether, tetrahydrofuran, hexane or cyclohexane.

(c) In order to prepare a compound of general formula

wherein R³ to R⁵ are as hereinbefore defined, Z¹ denotes the hydrogen atom or a protective group, for example a C₁₋₅-alkyloxycarbonyl or benzyloxycarbonyl group, and B′ denotes a group of formula

wherein R⁸ is as hereinbefore defined:

coupling and subsequent cyclisation of a compound of general formula

wherein n and R⁸ are as hereinbefore defined, with a compound of general formula

wherein R³ to R⁵ are as hereinbefore defined, Z¹ denotes a protective group, for example a C₁₋₅-alkyloxycarbonyl or benzyloxycarbonyl group, and Z⁴ denotes a nucleofugic leaving group, for example a chlorine, bromine or iodine atom, a tosylate, triflate or mesylate group, after which the protective group Z¹ is cleaved by methods known from the literature.

The reaction sequence is conveniently carried out in a solvent or mixture of solvents such as water, ethanol, isopropanol, benzene, chlorobenzene, toluene, xylene, glycol, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane or N-ethyl-diisopropylamine, N—C₁₋₅-alkylmorpholine, N—C₁₋₅-alkylpiperidine, N—C₁₋₅-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between −30 and 250° C., but preferably between 0 and 150° C., optionally conveniently in the presence of bases such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium-tert.-butoxide, sodium ethoxide, potassium hexamethyldisilazane, sodium hydride or lithium diiso-propylamide.

(d) In order to prepare a compound of general formula

wherein A, R¹ and R² are as hereinbefore defined and Q denotes a halogen atom or a hydroxy, C₁₋₄-alkoxy or C₁₋₄-acyloxy group:

-   -   i) nucleophilic substitution of a compound of general formula         A′-H,  (XIV)     -   wherein A′ denotes a 5- to 7-membered cycloalkyleneimino group         as mentioned hereinbefore under the definition of A, at the         aromatic group of general formula

-   -   wherein R¹ and R² are as hereinbefore defined and Z² denotes the         nitrile group or a C₁₋₅-alkoxycarbonyl group, and subsequent         saponification of the nitrile or C₁₋₅-alkoxycarbonyl group Z²         and optionally further reaction of the resulting carboxyl group         to form a reactive carboxylic acid derivative of general formula         XIII.

The nucleophilic substitution is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, benzene, chlorobenzene, toluene, xylene, glycol, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane or N-ethyl-diisopropylamine, N—C₁₋₅-alkylmorpholine, N—C₁₋₅-alkylpiperidine, N—C₁₋₅-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between −30 and 250° C., but preferably between 0 and 150° C., optionally conveniently in the presence of bases such as potassium carbonate, sodium carbonate, potassium-tert.-butoxide, sodium ethoxide, potassium hexamethyldisilazane, sodium hydride or lithium diisopropylamide.

-   -   ii) transition metal-catalysed coupling reaction of a compound         of general formula         A′-H,  (XIV)     -   wherein A′ denotes a 5- to 7-membered cycloalkyleneimino group         as mentioned hereinbefore under the definition of A, at the         aromatic group of general formula

-   -   wherein R¹ and R² are as hereinbefore defined and Z² denotes the         nitrile group or a C₁₋₅-alkoxycarbonyl group and Z³ denotes a         chlorine, bromine or iodine atom or a triflate group, and         subsequent saponification of the nitrile or C₁₋₅-alkoxycarbonyl         group Z² and optionally further reaction of the resulting         carboxyl group to form a reactive carboxylic acid derivative of         general formula XIII.

The reaction is expediently carried out in a solvent or mixture of solvents such as benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, tert.-butyl-methyl-ether, ethyleneglycoldimethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethyl sulphoxide, methylene chloride, chloroform or tetrachloromethane, for example at temperatures between −30 and 250° C., but preferably between 0 and 150° C., conveniently in the presence of transition metal catalysts such as nickel on activated charcoal, palladium charcoal, tetrakis-(triphenylphosphine)-palladium (0), tris-(dibenzylideneacetone)-dipalladium (0), palladium (II)acetate, palladium (II)chloride, bis-(triphenylphosphine)-palladium (II)-chloride, bis-(tricyclohexylphosphine)-palladium (II)-chloride, bis-(triethylphosphine)-palladium (II)-chloride, bis-(tri-o-tolylphosphine)-palladium (II)-chloride, optionally in the presence of ligands such as triphenylphosphine, tri-o-tolylphosphine, tri-tert.-butylphosphine, 1,3-bis-(diphenylphosphino)-propane, 2,2′-bis-(diphenyl-phosphino)-1,1′-dinaphthyl, 1,1′-bis-(diphenylphosphino)-ferrocene, xantphos, and conveniently in the presence of a base such as sodium methoxide, sodium ethoxide, sodium-tert.-butoxide, potassium-tert.-butoxide, sodium-tert.-butyldimethyl-silanoate, potassium hexamethyldisilazane, lithium diisopropylamide, potassium carbonate, rubidium carbonate, caesium carbonate, potassium phosphate, sodium hydride, optionally in the presence of a complexing agent such as 18-crown-6-ether as well as conveniently using an inert gas atmosphere (for example nitrogen or argon) and optionally under pressure.

-   -   iii) Selective oxidation of a cycloalkyleneimino group in         compounds of general formula

-   -   wherein A′ denotes a 5- to 7-membered, optionally also         substituted, 2-oxo-cycloalkyleneimine group as mentioned         hereinbefore under the definition of A, R¹ and R² are as         hereinbefore defined and Z² denotes the carboxyl group, and         optionally further reacting to form a reactive carboxylic acid         derivative of general formula XIII.

The reaction of a compound of general formula XIII obtained for example by the processes described hereinbefore, wherein A′ denotes a cycloalkyleneimino group and Q denotes the hydroxy group, to form the corresponding lactam by oxidation of a methylene group adjacent to the nitrogen is carried out for example with oxidising agents such as potassium permanganate, potassium chromate, potassium dichromate, chromium (VI)oxide, mercury (II)chloride, selenium (IV)oxide, lead (IV)oxide, lead (II,IV)oxide, potassium peroxomonosulphate, hydrogen peroxide, sodium hypochlorite, optionally in the presence of a suitable catalyst such as nickel (II)chloride, cobalt (II)chloride, ruthenium (III)chloride, osmium (VIII)oxide, vanadium (IV)oxide and/or in the presence of a crown ether such as 18-crown-6, in a solvent or mixture of solvents such as water, formic acid, acetic acid, ethyl acetate, benzene, pyridine, dichloromethane, chloroform, tetrachloromethane, optionally under 2-phase conditions in the presence of a suitable phase transfer catalyst such as for example tetrabutylammonium chloride, tetrabutylammonium bromide, benzyl-triethyl-ammonium chloride or methyl-trioctyl-ammonium chloride, optionally in the presence of an acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, sodium hydrogen sulphate, sodium dihydrogen phosphate and/or a base such as sodium hydroxide, potassium hydroxide, ammonia, pyridine, potassium phosphate, dipotassium hydrogen phosphate or sodium acetate at temperatures between −30 and 250° C., but preferably between 0 and 150° C. For example this reaction may be carried out as described by J. H. Markgraf, C. A. Stickney, J. Heterocycl. Chem. 2000, 37(1), 109.

-   -   iv) transition metal-catalysed coupling reaction of a compound         of general formula         A′-H,  (XIV)     -   wherein A′ denotes a 5- to 7-membered, optionally substituted         2-oxo-cycloalkyleneimino group as mentioned hereinbefore under         the definition of A, at the aromatic group of general formula

-   -   wherein R¹ and R² are as hereinbefore defined and Z² denotes the         nitrile group or a C₁₋₅-alkoxycarbonyl group and Z³ denotes a         chlorine, bromine or iodine atom or a triflate group, and         subsequent saponification of the nitrile or C₁₋₅-alkoxycarbonyl         group Z² and optionally further reaction of the resulting         carboxyl group to form a reactive carboxylic acid derivative of         general formula XII.

The reaction is expediently carried out in a solvent or mixture of solvents such as benzene, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, tert.-butyl-methyl-ether, ethyleneglycoldimethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide, methylene chloride, chloroform or tetrachloromethane, for example at temperatures between −30 and 250° C., but preferably between 0 and 200° C., conveniently in the presence of transition metal catalysts such as tetrakis-(triphenylphosphine)-palladium (0), tris-(dibenzylideneacetone)-dipalladium (0), palladium (II)acetate, palladium (II)chloride, bis-(triphenylphosphine)-palladium (II)-chloride, bis-(tricyclohexylphosphine)-palladium (II)-chloride, bis-(triethylphosphine)-palladium (II)-chloride, bis-(tri-o-tolylphosphine)-palladium (II)-chloride, optionally in the presence of ligands such as triphenylphosphine, tri-o-tolylphosphine, tri-tert.-butylphosphine, 1,3-bis-(diphenylphosphino)-propane, 2,2′-bis-(diphenylphosphino)-1,1′-dinaphthyl, 1,1′-bis-(diphenylphosphino)-ferrocene, xantphos, or for example in the presence of a transition metal catalyst such as copper (I)-iodide, copper (I)-bromide or copper (I)-acetate and conveniently in the presence of a base such as tetramethylguanidine, tetramethylethylenediamine or N,N′-dimethylethylenediamine and conveniently in the presence of a base such as sodium methoxide, sodium ethoxide, sodium-tert.-butoxide, potassium-tert.-butoxide, sodium-tert.-butyldimethyl-silanoate, potassium hexamethyldisilazane, lithium diisopropylamide, potassium carbonate, rubidium carbonate, caesium carbonate, potassium phosphate, sodium hydride, optionally in the presence of a complexing agent such as 18-crown-6-ether and conveniently using an inert gas atmosphere (for example nitrogen or argon) and optionally under pressure.

-   -   v) Acylation/sulphonylation and alkylation of a compound of         general formula

-   -   wherein R¹ and R² are as hereinbefore defined and Z² denotes the         nitrile group or a C₁₋₅-alkoxycarbonyl group, with a compound of         general formula

-   -   wherein E denotes a carbonyl, oxycarbonyl, sulphonyl or a         sulphamoyl group optionally substituted at the nitrogen atom as         mentioned hereinbefore, G denotes a chlorine, bromine or iodine         atom or an anhydride, C₁₋₅-alkoxy or benzotriazoloxy group or E         and G together denote an isocyano group and Z⁴ denotes a         nucleofugic leaving group, for example a chlorine, bromine or         iodine atom, a tosylate, triflate or mesylate group, and n is a         number between 3 and 5, while individual methylene groups         according to the description mentioned hereinbefore may         additionally be substituted or replaced by heteroatoms, and         subsequent intramolecular cyclisation by alkylation of the         anilide nitrogen while cleaving the nucleofugic leaving group         Z⁴, followed by saponification of the nitrile or         C₁₋₅-alkoxycarbonyl group Z² and optionally further reaction of         the resulting carboxyl group to form a reactive carboxylic acid         derivative of general formula XIII.

The acylation/sulphonylation is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane, N-ethyl-diisopropylamine, N—C₁₋₅-alkylmorpholine, N—C₁₋₅-alkylpiperidine, N—C₁₋₅-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between −30 and 250° C., but preferably between 0 and 150° C., conveniently in the presence of bases such as pyridine, triethylamine, p-dimethylaminopyridine, potassium carbonate, sodium carbonate, potassium-tert.-butoxide, sodium methoxide, sodium ethoxide or basic ion exchanger.

The subsequent intramolecular alkylation is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, dimethylsulphoxide, sulpholane, methylene chloride, tetrachloromethane, N-ethyl-diisopropylamine, N—C₁₋₅-alkylmorpholine, N—C₁₋₅-alkylpiperidine, N—C₁₋₅-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between −30 and 250° C., but preferably between 0 and 150° C., conveniently in the presence of bases such as pyridine, triethylamine, potassium carbonate, sodium carbonate, potassium-tert.-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hexamethyldisilazane or lithium diisopropylamide.

-   -   vi) carbamoylation/urea formation with a compound of general         formula

-   -   wherein R¹ and R² are as hereinbefore defined and Z² denotes the         nitrile group or a C₁₋₅-alkoxycarbonyl group, and which may be         obtained by methods known from the literature from compounds of         general formula XVIII, for example by reaction with phosgene in         toluene, with a compound of general formula

-   -   wherein Z⁴ denotes a nucleofugic leaving group, for example a         chlorine, bromine or iodine atom, a tosylate, triflate or         mesylate group, and E denotes a hydroxyl, amino or         C₁₋₃-alkylamino function and n is a number between 2 and 4,         while individual methylene groups may additionally be         substituted according to the description mentioned hereinbefore,         and subsequent intra-molecular cyclisation by alkylation of the         anilide nitrogen while cleaving the nucleofugic leaving group         Z⁴, followed by saponification of the nitrile or         C₁₋₅-alkoxycarbonyl group Z² and optionally further reaction of         the resulting carboxyl group to form a reactive carboxylic acid         derivative of general formula XIII.

The carbamoylation is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane, N-ethyl-diisopropylamine, N—C₁₋₅-alkylmorpholine, N—C₁₋₅-alkylpiperidine, N—C₁₋₅-alkylpyrrolidine, triethylamine, pyridine, for example at temperatures between −30 and 250° C., but preferably between 0 and 150° C. The subsequent intramolecular alkylation is carried out for example analogously to the method described under v).

-   -   vii) cyclisation metathesis of a compound of general formula

-   -   wherein R¹ and R² are defined as described hereinbefore, Z²         denotes a nitrile, C₁₋₅-alkoxycarbonyl or carboxyl group, E         denotes an aminocarbonyl, aminosulphonyl or amino group         optionally substituted according to the description mentioned         hereinbefore or a carbonyl or sulphonyl group or an oxygen or         sulphur atom or a bond, while m and o independently of one         another denote identical or different numbers between 1 and 3         which may be obtained by a sequence of alkylation and         acylation/sulphonylation/carbamoylation/sulphamoylation with         corresponding reagents by the methods already described herein         or known from the literature, followed by saponification of the         nitrile or C₁₋₅-alkoxycarbonyl group Z² and optionally further         reaction of the resulting carboxyl group to obtain a reactive         carboxylic acid derivative of general formula XIII.

The cyclisation by a reaction of metathesis is conveniently carried out in a solvent or mixture of solvents such as benzene, chlorobenzene, toluene, xylene, methanol, ethanol, propanol, diethyl ether, tert.-butyl-methyl-ether, tetrahydrofuran, dioxane, glycoldimethylether, diethyleneglycoldimethylether, dimethylformamide, N-methylpyrrolidinone, tetralin, dimethylsulphoxide, sulpholane, methylene chloride, chloroform, tetrachloromethane, pyridine, in the presence of a catalyst such as benzylidene-bis-(tricyclohexylphosphine)-dichloro-ruthenium (1st generation Grubbs catalyst) or benzylidene-[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro-(tricyclohexylphosphine)-ruthenium (2nd generation Grubbs catalyst) for example at temperatures between −30 and 250° C., but preferably between 0 and 150° C., conveniently under an inert gas atmosphere, for example argon.

(e) In order to prepare a compound of general formula

wherein A, B and R¹ to R⁵ are as hereinbefore defined:

acylation of a compound of general formula

wherein B and R³ to R⁵ are as hereinbefore defined and Z¹ denotes the hydrogen atom,

with a carboxylic acid or a reactive carboxylic acid derivative of general formula

wherein A, R¹ and R² are as hereinbefore defined and Q denotes a hydroxy or C₁₋₄-alkoxy group, a halogen atom or an acyloxy group.

The acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, sodium hydroxide solution or sulpholane, optionally in the presence of an inorganic or organic base at temperatures between −20 and 200° C., but preferably at temperatures between −10 and 160° C.

The acylation may, however, also be carried out with the free acid, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N-dicyclohexyl carbodiimide, N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N,N′-carbonyldiimidazole, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate/N-methylmorpholine, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate/N-ethyldiisopropylamine, apentafluorophenyl-N,N,N′,N′-tetramethyluronium hexafluorophosphate/triethylamine, N,N′-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, at temperatures between −20 and 200° C., but preferably at temperatures between −10 and 160° C.

Other methods of amide coupling are described for example in P. D. Bailey, I. D. Collier, K. M. Morgan in “Comprehensive Functional Group Interconversions”, Vol. 5, page 257ff, Pergamon 1995.

(f) In order to prepare a compound of general formula (II), (XXIV), (VII), (VIII), (XI) or (XXIII), wherein A, B and R¹ to R⁷ are as hereinbefore defined and R⁸ denotes a C₂₋₃-alkynyl group which is linked to the aromatic group via the carbon atom, and which simultaneously carries the triple bond, from a corresponding compound wherein R⁸ denotes a bromine or iodine atom or the triflate, boric acid or boric acid ester group:

-   transition metal-catalysed coupling reaction of a compound of     general formula

-   wherein Z⁵ denotes the hydrogen atom, the methyl group or a     protective group such as for example a trimethylsilyl,     tert.-butyl-dimethylsilyl, tert.-butyl-diphenylsilyl or triisopropyl     group, which can then be cleaved, -   with a compound of general formula (II), (XXIV), (VII), (VIII), (XI)     or (XXIII), wherein A, B and R¹ to R⁷ are as hereinbefore defined     and R⁸ denotes a bromine or iodine atom or the triflate, boric acid     or boric acid ester group.

The reaction is preferably carried out in a solvent or mixture of solvents such as acetonitrile, diethyl ether, tetrahydrofuran, dioxane, water or dimethylformamide or a mixture of solvents in the presence of a palladium catalyst such as for example bis(triphenylphosphine)-palladium (II)chloride, palladium (II)-[1,1′-bis-(diphenylphosphino)ferrocene]-chloride or tetrakis-(triphenylphosphine)-palladium (0) in the presence of a base such as triethylamine, N-isopropyl-diethylamine, N,N-diisopropyl-ethylamine, potassium-tert.-butoxide, sodium carbonate or caesium carbonate, optionally in the presence of ligands such as triphenylphosphine, tri-o-tolylphosphine, tri-tert.-butylphosphine, 1,3-bis-(diphenylphosphino)-propane, 2,2′-bis-(diphenylphosphino)-1,1′-dinaphthyl, 1,1′-bis-(diphenylphosphino)-ferrocene, xantphos and optionally in the presence of a transition metal compound such as a copper halide such as for example copper (I)iodide and at temperatures between 20 and 120° C., preferably at temperatures between 20 and 90° C. under argon or nitrogen atmosphere (cf. also K. Sonogashira, Comprehensive Organic Synthesis, Vol. 3, page 52ff., Pergamon Press, Oxford 1991).

Any silyl protective group present such as for example trimethylsilyl is preferably cleaved in a solvent or mixture of solvents such as water, methanol, ethanol, isopropanol, acetone, dioxane, tetrahydrofuran or dimethylformamide in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide. For cleaving in organic solvents such as for example diethyl ether, tetrahydrofuran, dimethylformamide or dichloromethane it is also possible to use fluoride reagents, such as for example tetrabutylammonium fluoride, lithium fluoride or potassium fluoride, optionally with the addition of a complexing agent such as 18-crown-6-ether.

In the reactions described above any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction. For example, a suitable protecting group for a hydroxy group may be the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,

-   suitable protecting groups for a carboxyl group might be the     trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or     tetrahydropyranyl group, -   suitable protecting groups for an amino, alkylamino or imino group     might be the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,     tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or     2,4-dimethoxybenzyl group and additionally, for the amino group, the     phthalyl group.

Other protective groups and their cleaving are described in T. W. Greene, P. G. M. Wuts, “Protecting Groups in Synthesis”, Wiley, 1991 and 1999.

Any protecting group used may optionally subsequently be cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved hydrogenolytically, for example, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50° C., but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably, however, 1 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium (IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures of between 0 and 50° C., but preferably at ambient temperature.

A methoxy group is expediently cleaved in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between −35 and −25° C.

A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisol.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50° C.

An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium (0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100° C., preferably at ambient temperature and under an inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium (I)chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70° C.

Compounds of general formulae (II), wherein the group B′ is represented by a group of general formula (III), and (IV) may be prepared for example analogously to K. Maekawa, J. Ohtani, Agr. Biol. Chem. 1976, 40, 791-799.

Moreover the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers.

Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (−)-menthol and an optically active acyl group in amides may be a (+)- or (−)-menthyloxycarbonyl, for example.

Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

As already mentioned, the compounds of general formula I as well as the tautomers, the enantiomers, the diastereomers and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an antithrombotic activity, which is preferably based on an effect on thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on a prolonging effect on the aPTT time and/or on an inhibiting effect on related serine proteases such as e.g. urokinase, factor VIIa, factor IXa, factor XIa and factor XIIa.

The compounds listed in the experimental section were investigated for their effect on the inhibition of factor Xa as follows:

Method:

Enzyme-kinetic measurement with chromogenic substrate. The quantity of p-nitroaniline (pNA) released from the colourless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance (in relation to the solvent control) is determined at various concentrations of test substance and from this the IC₅₀ is calculated, as the concentration which inhibits the factor Xa used by 50%.

Material:

Tris(hydroxymethyl)-aminomethane buffer (100 mMol) and sodium chloride (150 mMol), pH 8.0 plus 1 mg/ml Human Albumin Fraction V, protease-free Factor Xa (Calbiochem), spec. activity: 217 IU/mg, final concentration: 7 IU/ml for each reaction mixture

Substrate S 2765 (Chromogenix), final concentration: 0.3 mM/I (1 KM) for each reaction mixture

Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 μMol/l

Procedure:

10 μl of a 23.5-times concentrated starting solution of the test substance or solvent (control), 175 ml of TRIS/HSA buffer and 25 μl of a 65.8 U/L Factor Xa working solution are incubated for 10 minutes at 37° C. After the addition of 25 μl of S 2765 working solution (2.82 mMol/l) the sample is measured in a photometer (SpectraMax 250) at 405 nm for 600 seconds at 37° C.

Evaluation:

-   1. Determining the maximum increase (deltaOD/minutes) over 21     measuring points. -   2. Determining the % inhibition based on the solvent control. -   3. Plotting a dosage/activity curve (% inhibition vs substance     concentration). -   4. Determining the IC₅₀ by interpolating the X-value (substance     concentration) of the dosage/activity curve at Y=50% inhibition.

All the compounds tested had an IC₅₀ value of less than 100 μmol/L.

The compounds prepared according to the invention are generally well tolerated.

In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the prevention and treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases, and for preventing and treating pulmonary embolism, disseminated intravascular coagulation and severe sepsis, for preventing and treating DVT in patients with exacerbation of COPD, for treating ulcerative colitis, for treating and preventing coronary thrombosis, for preventing stroke and the occlusion of shunts. In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase, for preventing long-term restenosis after PT(C)A, for the prevention and treatment of ischaemic incidents in patients with all forms of coronary heart disease, for preventing metastasis and the growth of tumours and inflammatory processes, e.g. in the treatment of pulmonary fibrosis, for preventing and treating rheumatoid arthritis, for preventing and treating fibrin-dependent tissue adhesions and/or the formation of scar tissue and for promoting wound healing processes. The new compounds and the physiologically acceptable salts thereof may be used therapeutically in conjunction with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the clotting system and the recombinant analogues thereof (e.g. Protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, ticlopidine), with P₂T receptor antagonists (e.g. cangrelor) or with combined thromboxane receptor antagonists/synthetase inhibitors (e.g. terbogrel).

The dosage required to achieve such an effect is appropriately 0.01 to 3 mg/kg, preferably 0.03 to 1.0 mg/kg by intravenous route, and 0.03 to 30 mg/kg, preferably 0.1 to 10 mg/kg by oral route, in each case administered 1 to 4 times a day.

For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

The Examples which follow are intended to illustrate the invention without restricting its scope:

EXPERIMENTAL SECTION

As a rule, melting points, IR, UV, ¹H-NMR and/or mass spectra have been obtained for the compounds prepared. Unless otherwise stated, R_(f) values were obtained using ready-made silica gel 60 F₂₅₄ TLC plates (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation. The R_(f) values obtained under the name Alox were determined using ready-made aluminium oxide 60 F₂₅₄ TLC plates (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation. The R_(f) values obtained under the name Reversed-phase-8 were determined using ready-made RP-8_(F254s) TLC plates (E. Merck, Darmstadt, Item no. 1.15684) without chamber saturation. The ratios given for the eluants refer to units by volume of the solvent in question. Chromatographic purification was done using silica gel supplied by Messrs Millipore (MATREX™, 35-70 μm). If the configuration is not specified in detail, it is unclear whether the compound in question is a pure stereoisomer or a mixture of enantiomer and diastereomer.

The following abbreviations are used in the descriptions of the tests:

-   Boc tert.-butoxycarbonyl -   DIPEA N-ethyl-diisopropylamine -   DMSO dimethylsulphoxide -   DMF N,N-dimethylformamide -   sat. saturated -   h hour(s) -   i. vac. in vacuo -   conc. concentrated -   NMM N-methyl-morpholine -   NMP N-methyl-pyrrolidin-2-one -   o ortho -   PfTU O-pentafluorophenyl-N,N,N′,N′-etramethyluronium     hexafluorophosphate -   PPA propanephosphonic cycloanhydride -   quant. quantitative -   R_(f) retention factor -   R_(t) retention time -   rac. racemic -   TBTU O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium     tetrafluoroborate -   TEA triethylamine -   TFA trifluoroacetic acid -   THF tetrahydrofuran -   tert. tertiary -   Σ yield over all the steps carried out analogously as described

The HPLC/MS data for Examples 35 to 38 were obtained under the following conditions:

-   (a) Waters ZMD, Alliance 2690 HPLC, Waters 2700 Autosampler, Waters     996 diode array detector

The following was used as the mobile phase:

-   A: water with 0.1% trifluoroacetic acid -   B: acetonitrile with 0.1% trifluoroacetic acid

time in min % A % B flow rate in ml/min 0.0 95 5 1.00 0.1 95 5 1.00 5.1 2 98 1.00 6.5 2 98 1.00 7.0 95 5 1.00

The stationary phase used was a Waters column X-Terra™ MS C₁₈ 3.5 μm, 4.6 mm×50 mm (column temperature: constant at 25° C.)

The diode array detection took place in a wavelength range from 210-500 nm Range of mass-spectrometry detection: m/z 120 to m/z 950

-   (b) The HPLC/MS data for the other Examples, if provided, were     obtained under the following conditions: -   HP 1100 with quarternary pump, Gilson G215 Autosampler, HP diode     array detector.

The mobile phase used was:

-   A: water with 0.1% TFA -   B: acetonitrile with 0.08% TFA

time in min % A % B flow rate in ml/min 0.0 95 5 0.4 0.15 95 5 0.4 4.65 2 98 0.4 6.0 2 98 0.4 6.5 95 5 0.4

The stationary phase used was a Waters column X-Terra™ MS C₁₈ 2.5 μm, 2.1 mm×50 mm (column temperature: constant at 25° C.)

The diode array detection took place in a wavelength range from 210-550 nm Range of mass-spectrometry detection: m/z 120 to m/z 1000.

Example 1 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]diazepan-1-yl)-benzamide

(a) 4-(4-N-acetyl-[1,4]diazepan-1-yl)-3-chloro-benzonitrile

4.67 g (30 mmol) 3-chloro-4-fluoro-benzonitrile and 4.27 g (30 mmol) N-1-acetyl-[1,4]diazepan are stirred in 5.0 ml DIPEA for 6 hours at 90° C. Then the mixture is evaporated down i. vac. and the residue is dissolved in dichloromethane. The organic phase is washed twice with water, dried over sodium sulphate and evaporated down i. vac. The residue is further reacted without any more purification.

Yield: 7.50 g (90%)

R_(f) value: 0.20 (silica gel; dichloromethane/ethanol=50:1)

(b) 3-chloro-4-([1,4]diazepan-1-yl)-benzoic acid

The residue obtained in Example 1a (7.50 g, 27.0 mmol) is refluxed for 8 h in 50 ml 25% potassium hydroxide solution. Then the mixture is adjusted to pH 5 with conc. hydrochloric acid. The solid precipitated is filtered off, dried and further reacted without any more purification.

Yield: 5.60 g (81%)

R_(f) value: 0.0 (silica gel; dichloromethane/ethanol=9:1)

(c) methyl 3-chloro-4-([1,4]diazepan-1-yl)-benzoate

The residue obtained in Example 1b (3.00 g, 11.8 mmol) is suspended in 100 ml of methanol and hydrogen chloride is piped in over 1 hour with stirring and heating to reflux temperature. Then the mixture is evaporated down i. vac., the residue is combined with 5% sodium hydrogen carbonate solution and extracted 3 times with dichloromethane. The combined organic phases are dried over sodium sulphate. The residue remaining after evaporation i. vac. is further reacted without any more purification.

Yield: 2.25 g (71%)

R_(f) value: 0.10 (silica gel; dichloromethane/ethanol=4:1+2% ammonia)

C₁₃H₁₇ClN₂O₂ (268.75)

Mass spectrum: (M+H)⁺=269/271 (chlorine isotope)

(d) methyl 4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoate

The residue obtained in Example 1c (1.00 g, 3.72 mmol) is combined with 0.53 g (3.80 mmol) potassium carbonate in 10 ml dichloromethane and then 0.83 g (3.80 mmol) di-tert. butyl pyrocarbonate are added dropwise. Then the mixture is stirred for 16 hours at ambient temperature. Then it is diluted with dichloromethane, washed twice with water, dried over sodium sulphate and evaporated down i. vac. Purification by chromatography on silica gel is then carried out (eluant: methylene chloride/ethanol 99:1).

Yield: 1.34 g (98%)

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=50:1)

C₁₈H₂₅ClN₂O₄ (368.86)

Mass spectrum: (M+H)⁺=369/371 (chlorine isotope)

(e) 4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoic acid

0.60 g (1.63 mmol) methyl 4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoate are dissolved in 10 ml of methanol, combined with 4 ml 2-molar potassium hydroxide solution and stirred for 3 hours at 40° C. Then the mixture is evaporated down i. vac., the residue is diluted with distilled water, acidified with saturated potassium hydrogen sulphate solution and extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The residue is further reacted without any more purification.

Yield: 0.50 g (87%)

R_(f) value: 0.05 (silica gel; dichloromethane/ethanol=50:1)

C₁₇H₂₃ClN₂O₄ (354.84)

(f) 4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-benzamide

532 mg (1.50 mmol) 4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-benzoic acid are suspended in 15 ml THF and after the addition of 546 mg (1.70 mmol) TBTU and 646 mg (5.0 mmol) DIPEA stirred for 30 minutes at ambient temperature. Then 403 mg (1.50 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine-dihydrochloride are added and the mixture is stirred for a further 16 hours at ambient temperature. It is then evaporated down i. vac., the residue is dissolved in ethyl acetate, the organic phase is washed with 5% sodium hydrogen carbonate solution and water and dried over sodium sulphate. After evaporation i. vac. the residue remaining is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate: 90:10->60:40).

Yield: 630 mg (79%)

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=19:1)

C₂₆H₃₁Cl₂N₅O₃ (532.48)

Mass spectrum: (M+H)⁺=532/534/536 (chlorine isotope)

(g) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]diazepan-1-yl)-benzamide

A solution of 610 mg (1.15 mmol) 4-(4-N-Boc-[1,4]diazepan-1-yl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-benzamide in 30 ml dichloromethane is combined with 3 ml TFA and stirred for 3 hours at ambient temperature. Then it is evaporated down i. vac., the residue is taken up in ethyl acetate, washed with 5% sodium hydrogen carbonate solution and water and dried over sodium sulphate. After evaporation i. vac. the residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 80:20->50:50).

Yield: 380 mg (77%)

R_(f) value: 0.10 (silica gel; dichloromethane/ethanol=9:1)

C₂₁H₂₃Cl₂N₅O (432.36)

Mass spectrum: (M+H)⁺=432/434/436 (chlorine isotope)

The following compound was prepared analogously:

structural formula No. Name yield mass peak(s) R_(f) value/R_(t) value 115

Σ: 13% (M + H)⁺ = 462/464/466 (chlorine isotope) 0.13 (silica gel, dichloromethane/ methanol = 9:1) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-chloro-4-([1,4]-diazepan-1-yl)-benzamide

Example 2 4-(4-N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide

(a) 4-(piperazin-1-yl)-3-trifluoromethyl-benzoic acid

37.9 g (195 mmol) piperazine hexahydrate are refluxed for 2 hours with 12.4 g (66 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile suspended in 40 ml of ethanol. Then 13.7 ml (261 mmol) 50% sodium hydroxide solution and 13.7 ml of water are added and the mixture is refluxed for a further 3.5 hours and kept at ambient temperature for a further 15 hours. Then 43.5 ml of conc. hydrochloric acid are added and the mixture is cooled to 10° C. for 30 minutes with stirring. The precipitate obtained is suction filtered, washed with a little water and dried at 40° C. in the circulating air dryer for 24 hours.

Yield: 20.8 g (quantitative)

(b) methyl 4-(piperazin-1-yl)-3-trifluoromethyl-benzoate

5.00 g (18.2 mmol) 4-(piperazin-1-yl)-3-trifluoromethyl-benzoic acid are stirred 16 hours in 50 ml of methanolic hydrochloric acid. After evaporation of the reaction mixture i. vac. the residue is stirred with isopropanol. The solid is filtered off, washed with diethyl ether and dried at 60° C. in the circulating air dryer.

Yield: 5.00 g (76%)

C₁₃H₁₅F₃N₂O₂.2HCl (288.27/361.19)

Mass spectrum: (M+H)⁺=289

R_(f) value: 0.58 (silica gel; cyclohexane/dichloromethane/methanol=70:15:15+2% conc. ammonia solution)

(c) methyl 4-(4-N-Boc-piperazin-1-yl)-3-trifluoromethyl-benzoate

5.77 g (11.78 mmol) methyl 4-(piperazin-1-yl)-3-trifluoromethyl-benzoate are placed in 100 ml THF and combined with 4.47 g (20.5 mmol) di-tert. butyl pyrocarbonate. After 40 hours stirring at ambient temperature under a nitrogen atmosphere the reaction mixture is evaporated down i. vac., the residue is combined with water and sat. sodium chloride solution and extracted with ethyl acetate. The combined organic phases are washed with water, semisaturated and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 9:1->8:1).

Yield: 2.60 g (34%)

R_(f) value: 0.52 (silica gel; petroleum ether/ethyl acetate 7:3+1% conc. ammonia solution)

C₁₈H₂₃F₃N₂O₄ (388.39)

Mass spectrum: (M+H)⁺=389

(d) 4-(4-N-Boc-piperazin-1-yl)-3-trifluoromethyl-benzoic acid

2.60 g (6.69 mmol) methyl 4-(4-N-tert.-butoxylcarbonyl-piperazin-1-yl)-3-trifluoromethyl-benzoate are dissolved in 10 ml of methanol and combined with 12.3 ml (12.3 mmol) 1-molar sodium hydroxide solution. After 15 minutes a further 10 ml of methanol are added and the reaction mixture is stirred for 42 hours at ambient temperature. Then the mixture is evaporated down i. vac., the residue is combined with ice and acidified with acetic acid. The precipitate obtained is suction filtered, washed with water and dried in the circulating air dryer at 50° C. and in the drying pistol at 40° C. over KOH and SiO₂.

Yield: 2.40 g (96%)

R_(f) value: 0.41 (silica gel; petroleum ether/ethyl acetate=1:1+1% acetic acid)

C₁₇H₂₁F₃N₂O₄ (374.36)

Mass spectrum: (M−H)⁻=373

(e) 4-(4-N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide

Prepared analogously to Example 1f from 4-(4-N-Boc-piperazin-1-yl)-3-trifluoromethyl-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in NMP and subsequent purification by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=50:50).

Yield: 57%

R_(f) value: 0.20 (silica gel; petroleum ether/ethyl acetate=1:1)

C₂₆H₂₉ClF₃N₅O₃ (552.00)

Mass spectrum: (M+H)⁺=552/554 (chlorine isotope)

Example 3 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide

Prepared analogously to Example 1g from 4-(4-N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide and TFA in dichloromethane.

Yield: 73%

R_(f) value: 0.28 (silica gel; dichloromethane/methanol=90:10+ammonia solution)

C₂₁H₂₁ClF₃N₅O.2 CF₃COOH (679.93/451.88)

Mass spectrum: (M+H)⁺=452/454 (chlorine isotope)

The following were prepared analogously to the sequence described in Examples 2 and 3:

structural formula No. Name yield mass peak(s) R_(f) value  4

Σ: 14% (M + H)⁺ = 482/484 (chlorine isotope) 0.15 (silica gel, CH₃COOC₂H₅/ C₂H₅OH 9:1 + NH₃) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl)-4-(piperazin-1-yl)-3-trifluoromethyl- benzamide 40

Σ: 13% (M + H)⁺ = 512/514 (chlorine isotope) 0.20 (silica gel, CH₂Cl₂/ C₂H₅OH 9:1) N-[(1S)-1-(5-chloro-1H-benzmidazol-2-yl)-3-methylsulphanyl-propyl)-4-(piperazin-1-yl)-3-trifluoromethyl- benzamide

Example 5 4-(4-N-acetyl-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide

220 mg (0.32 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide-ditrifluoroacetate in 5 ml THF are combined with 0.23 ml (1.65 mmol) TEA, 50 μl (0.70 mmol) acetylchloride are added dropwise with stirring and cooling in the ice bath and stirred for 2 hours at ambient temperature. The reaction mixture is poured into ice water and then extracted with ethyl acetate. The organic phase is washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is triturated with a solvent mixture of ethyl acetate and diethyl ether, filtered off, washed with diethyl ether and dried in a drying pistol at 50° C.

Yield: 0.13 g (81%)

R_(f) value: 0.55 (silica gel; dichloromethane/ethanol=9:1+ammonia solution)

C₂₃H₂₃ClF₃N₅O₂ (493.92)

Mass spectrum: (M+H)⁺=494/496 (chlorine isotope)

Example 6 4-(azepan-2-on-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide

(a) methyl 4-(6-bromo-hexanoyl-amino)-3-methyl-benzoate

A solution of 2.14 g (10 mmol) 6-bromo-hexanoylchloride in 5.0 ml THF is slowly added dropwise with stirring at ambient temperature to 1.65 g (10 mmol) methyl 4-amino-3-methyl-benzoate in 50 ml THF with 2 ml DIPEA. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is dissolved in dichloromethane, washed twice with water and dried over sodium sulphate. The residue remaining after evaporation i. vac. is further reacted without any more purification.

Yield: 3.30 g (96%)

R_(f) value: 0.40 (silica gel; petroleum ether/ethyl acetate=4:1)

C₁₅H₂₀BrNO₃ (342.24)

(b) methyl 4-(azepan-2-on-1-yl)-3-methyl-benzoate

3.20 g (9.35 mmol) of the product obtained in Example 5a is refluxed for 4 hours in a freshly prepared solution of 1.00 g (43.5 mmol) sodium in 80 ml of methanol. Then the mixture is evaporated down i. vac., the residue is acidified with 2-molar acetic acid and extracted with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulphate. The residue obtained after evaporation i. vac. is further reacted without any more purification.

Yield: 1.90 g (contaminated product)

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=50:1)

C₁₅H₁₉NO₃ (261.32)

Mass spectrum: (M+H)⁺=262

(c) 4-(azepan-2-on-1-yl)-3-methyl-benzoic acid

1.90 g of the product obtained in Example 5b in 30 ml of methanol is combined with 10 ml 2-molar sodium hydroxide solution and stirred for 16 hours at ambient temperature. After evaporation i. vac. the residue is combined with water and acidified with conc. hydrochloric acid. The precipitate formed is filtered off and dried. After dissolving in methanol and applying to silica gel the product is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 70:30->50:50).

Yield: 0.23 g (10% over 2 steps)

R_(f) value: 0.10 (silica gel; petroleum ether/ethyl acetate=1:2)

C₁₄H₁₇NO₃ (247.30)

Mass spectrum: (M+H)⁺=248

(d) 4-(azepan-2-on-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide

Prepared analogously to Example 1f from 4-(azepan-2-on-1-yl)-3-methyl-benzoic acid, TBTU, DIPEA and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in THF and subsequent purification by chromatography on silica gel (eluting gradient: ethyl acetate/ethanol 95:5->90:10).

Yield: 61%

R_(f) value: 0.30 (silica gel; ethyl acetate)

C₂₃H₂₅ClN₄O₂ (424.93)

Mass spectrum: (M+H)⁺=425/427 (chlorine isotope)

The following compounds were prepared analogously:

structural formula No. Name yield mass peak(s) R_(f) value  7

Σ: 1.1% (M − H)⁻ = 453/455 (chlorine isotope) 0.60 (aluminum oxide, CH₂Cl₂/ C₂H₅OH 19:1) 4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-benzamide  8

Σ: 7.6% (M + H)⁺ = 441/443 (chlorine isotope) 0.20 (silica gel, CH₂Cl₂/ C₂H₅OH 19:1) 4-(azepan-2-on-1-yl)-N-[(1R)-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-benzamide 10

Σ: 72% (M + H)⁺ = 397/399 (chlorine isotope) 0.50 (silica gel, CH₂Cl₂/ C₂H₅OH 9:1) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(pyrrolidin-2-on-1-yl)-benzamide 11

Σ: 24% (M + H)⁺ = 457/459 (chlorine isotope) 0.63 (silica gel, CH₂Cl₂/ C₂H₅OH 9:1) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(pyrrolidin-2-on- 1-yl)-benzamide

Example 9 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrrolidin-2-on-1-yl)-benzamide

(a) 4-(pyrrolidin-2-on-1-yl)-benzoic acid

19.2 g (140 mmol) 4-amino-benzoic acid are refluxed for 20 hours together with 25.8 ml (180 mmol) ethyl 4-bromobutyrate in 100 ml DMF. After evaporation i. vac. the residue is combined with 100 ml of water and 50 ml petroleum ether and vigorously stirred for 50 minutes. The precipitate is filtered off, recrystallised from ethanol and dried at 80° C.

Yield: 9.36 g (33%)

C₁₁H₁₁NO₃ (205.22)

Mass spectrum: (M+H)⁺=206

(b) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(byrrolidin-2-on-1-yl)-benzamide

Prepared analogously to Example 1f from 4-(pyrrolidin-2-on-1-yl)-benzoic acid, TBTU, DIPEA and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine in THF and subsequent purification by washing the solution of the residue in ethyl acetate with water, dilute sodium hydrogen carbonate solution, water and sat. sodium chloride solution, drying over sodium sulphate and eliminating the solvent i. vac.

Yield: 61%

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=9:1)

C₂₀H₁₉ClN₄O₂ (382.85)

Mass spectrum: (M+H)⁺=383/385 (chlorine isotope)

Example 12 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzamide

(a) 3-chloro-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzonitrile

Prepared analogously to Example 1a from 3-chloro-4-fluoro-benzonitrile and 1-methyl-[1,4]diazepan in DIPEA with subsequent purification by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 98:2->94:6).

Yield: 71%

R_(f) value: 0.20 (silica gel; methylene chloride/ethanol=19:1)

C₁₃H₁₆ClN₃ (249.75)

Mass spectrum: (M+H)⁺=250/252 (chlorine isotope)

(b) 3-chloro-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid

Prepared analogously to Example 1b from 3-chloro-4-(4-methyl-[1,4]diazepan-1-yl)-benzonitrile in 25% aqueous potassium hydroxide solution.

Yield: 99%

C₁₃H₁₇ClN₂O₂.HCl (268.74/305.21)

Mass spectrum: (M+H)⁺=269/271 (chlorine isotope)

(c) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzamide

Prepared analogously to Example 1f from 3-chloro-4-(4-methyl-[1,4]diazepan-1-yl)-benzoic acid, (S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 50:50->20:80).

Yield: 34%

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=9:1+1% ammonia solution)

C₂₂H₂₅Cl₂N₅O (446.38)

Mass spectrum: (M+H)⁺=446/448/450 (chlorine isotope)

Example 13 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(2-methyl-pyrrolidin-1-yl)-benzamide

(a) 3-chloro-4-(2-methyl-pyrrolidin-1-yl]-benzonitrile

5.90 g (37.9 mmol) 3-chloro-4-fluoro-benzonitrile are dissolved in 65 ml DMF under a nitrogen atmosphere and combined with 5.45 g (39.5 mmol) potassium carbonate and 4.2 ml (3.5 g, 39.5 mmol) 2-methyl-pyrrolidine. After stirring for 2.5 days at 90° C. the reaction mixture is poured into 400 ml of water and extracted with ethyl acetate. The combined organic phases are washed several times with dilute and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac. The residue remaining is further reacted without any more purification.

Yield: 7.90 g (94%)

R_(f) value: 0.40 (silica gel; petroleum ether/ethyl acetate=9:1+0.5% ammonia solution)

C₁₂H₁₃ClN₂ (220.70)

Mass spectrum: (M+H)⁺=221/223 (chlorine isotope)

(b) 3-chloro-4-(2-methyl-pyrrolidin-1-yl)-benzoic acid

8.0 g (40 mmol) of the product obtained in Example 13a are stirred in a mixture of 65 ml 10-molar sodium hydroxide solution and 65 ml of ethanol for 2.75 hours at 90° C. Then the reaction mixture is poured into ice water, combined with conc. hydrochloric acid and volatile organic constituents are evaporated down i. vac. The aqueous phase remaining is extracted with dichloromethane, combined with ice and adjusted to pH 4.5 with semiconcentrated hydrochloric acid and 2-normal potassium hydrogen sulphate solution. The resulting precipitate is stirred for another 10 minutes, then filtered off, washed with water and dried at 55° C.

Yield: 8.30 g (87%)

R_(f) value: 0.55 (silica gel; petroleum ether/ethyl acetate=6:4+1% acetic acid)

C₁₂H₁₄ClNO₂ (238.72)

Mass spectrum: (M+H)⁺=240/242 (chlorine isotope)

(c) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl)-4-(2-methyl-pyrrolidin-1-yl)-benzamide

Prepared analogously to Example 1f from 3-chloro-4-(2-methyl-pyrrolidin-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and TEA in DMF, then precipitated by pouring into dilute sodium hydrogen carbonate solution, filtering and washing with water. Then the product is dried at 55° C.

Yield: 92%

R_(f) value: 0.66 (silica gel; dichloromethane/ethanol=9:1)

C₂₁H₂₂Cl₂N₄O (417.34)

Mass spectrum: (M−H)⁻=415/417/419 (chlorine isotope)

The following compounds were prepared analogously:

structural formula R_(f) value/R_(t) No. Name yield mass peak(s) value 14

Σ: 11% (M + H)⁺ = 419/421/423 (chlorine isotope) 0.55 (silica gel, petroleum ether/ CH₃COOC₂H₅ 19:1) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-chloro-4-(morpholin-4-yl)-benzamide 15

Σ: 19% (M + H)⁺ = 421/423 (chlorine isotope) 0.30 (silica gel, petroleum ether/ CH₃COOC₂H₅ 1:1) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3,5-difluoro-4-(morpholin-4-yl)-benzamide 16

Σ: 17% (M + H)⁺ = 483/485 (chlorine isotope) 3.46 min N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-4-(morpholin-4-yl)-benzamide 17

Σ: 13% (M + H)⁺ = 465/467 (chlorine isotope) 3.21 min 4-(azepan-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-trifluoromethyl-benzamide 18

Σ: 20% (M + H)⁺ = 431/433/435 (chlorine isotope 3.02 min 4-(azepan-1-yl)-3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-benzamide 19

Σ: 49% (M + H)⁺ = 417/419/421 (chlorine isotope) 0.47 (silica gel, CH₂Cl₂/ isopropanol 19:1) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-1-yl)-benzamide 20

Σ: 6.2% (M + H)⁺ = 433/435/437 (chlorine isotope) 2.61 min 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,4]oxazepan-4-yl)-benzamide 37

Σ: 9.4% (M + H)⁺ = 411/413 (chlorine/ isotope) 0.53 (silica gel, CH₂Cl₂/CH₃OH 19:1) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,5-dimethylpiperidin-1-yl)-benzamide 38

Σ: 20% (M − H)⁻ = 413/415/417 (chlorine isotope) 2.84 min 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,4-di-dehydro-piperidin-1-yl)-benzamide 50

Σ: 1.2% (M + H)⁺ = 529/531/533 (chlorine isotope) 0.29 (silica gel, CH₂Cl₂/ CH₃OH 9:1) 2.38 min 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-[2-(4-methyl- piperazin-1-yl-methyl)-piperidin-1-yl)-benzamide

Example 21 N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzamide

(a) 4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzoic acid

1.00 g (3.63 mmol) 4-(morpholin-4-yl)-3-trifluoromethyl-benzoic acid (prepared by synthesis sequence analogously to Example 13a and 13b) is suspended in 40 ml of water and 150 mg (3.75 mmol) sodium hydroxide are added. Then 1.73 g (10.92 mmol) potassium permanganate are added and the mixture is stirred for 1.5 hours at 45° C. Then the reaction mixture is cooled in the ice bath and sodium thiosulphate is added until total decolorisation is obtained. After extraction 3 times with ethyl acetate the combined organic phases are dried over sodium sulphate evaporated down i. vac. After application of the residue to silica gel it is purified by chromatography on silica gel (eluant: dichloromethane/methanol 95:5).

Yield: 340 mg (32%)

C₁₂H₁₀F₃NO₄ (289.21)

Mass spectrum: (M+H)⁺=290

(b) N′-(2-amino-4-chloro-phenyl)-N-Boc-(S)-O-methyl-serinamide and N′-(2-amino-5-chloro-phenyl)-N-Boc-(S)-O-methyl-serinamide

30.0 g (137 mmol) N-Boc-(S)-O-methyl-serine are dissolved together with 21.9 g (154 mmol) 4-chloro-1,2-phenylenediamine in 658 ml THF, and 43.9 ml (316 mmol) triethylamine and 103 ml (173 mmol) of a 50% solution of PPA in ethyl acetate are added with stirring in the ice bath. After 15 minutes stirring in the ice bath the mixture is heated to ambient temperature, poured into water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with sat. sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/methanol=30:1->9:1).

Yield: 33.47 g (72%) mixture of the two regioisomers

C₁₅H₂₂ClN₃O₄ (343.81)

Mass spectrum: (M−H)⁻=342/344 (chlorine isotope)

R_(f) value: 0.80 (silica gel; dichloromethane/methanol=9:1)

(c) (1R)-N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine

26.01 g (75.65 mmol) of the mixture obtained in Example 21b are dissolved in 1500 ml of toluene and 20.8 ml (364 mmol) acetic acid and 10.0 g molecular sieve, 4 Å, are added. The reaction mixture is stirred for 5 hours at 60° C. The reaction mixture is filtered, washed again with ethyl acetate and the organic phase is washed with semisat. sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated down i. vac. The residue is stirred with diethyl ether and the crystals formed are suction filtered. The filtrate is evaporated down i. vac. and the residue is purified by three lots of chromatography on silica gel (eluting gradient: dichloromethane/methanol 80:1->50:1).

Yield: 13.85 g (56%)

C₁₅H₂₀ClN₃O₃ (325.79)

Mass spectrum: (M+H)⁺=326/328 (chlorine isotope)

R_(f) value: 0.29 (silica gel; dichloromethane/methanol=30:1)

(d) (1R)-1-(5-chloro-1H-benzimidazol-1-yl)-2-methoxy-ethylamine

0.50 g (1.54 mmol) (1R)-N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine in 1.5 ml dichloromethane are combined with 1.54 ml (20.0 mmol) TFA and stirred for 2 h at ambient temperature. The mixture is then poured into sat. sodium hydrogen carbonate solution and after thorough mixing the aqueous phase is extracted with dichloromethane and ethyl acetate. The combined organic phases are dried over sodium sulphate and purified by chromatography on silica gel (eluant: dichloromethane/methanol=9:1+1% conc. ammonia solution).

Yield: 0.35 g (quant.)

C₁₀H₁₂ClN₃O (225.68)

Mass spectrum: (M−H)⁻=224/226 (chlorine isotope)

R_(f) value: 0.40 (silica gel, dichloromethane/methanol 9:1+1% conc. ammonia solution)

(e) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzamide

Prepared analogously to Example 1f from 4-(morpholin-3-on-4-yl)-3-trifluoromethyl-benzoic acid, (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and NMM in DMF, then precipitation by pouring into water, filtering and drying i. vac.

Yield: 63%

R_(f) value: 0.57 (silica gel; dichloromethane/methanol=9:1)

C₂₂H₂₀ClF₃N₄O₄ (496.88)

Mass spectrum: (M+H)⁺=497/499 (chlorine isotope)

The following compounds were prepared analogously:

structural formula No. Name Yield mass peaks(s) R_(f) value or R_(t) 25

Σ: 2.0% (M + H)⁺ = 475/477/479 (chlorine isotope) 2.57 min 4-(azepan-2-on-1-yl)-3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-benzamide 26

Σ: 29% (M + H)⁺ = 509/511 (chlorine isotope) 2.65 min 4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl- benzamide 44

Σ: 8.5% (M + H)⁺ = 477/479/481 (chlorine isotope) 0.47 (silica gel, CH₂Cl₂/CH₃OH 95:5) 2.37 min 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-5-on-4-yl)- benzamide 45

Σ: 2.2% (M + H)⁺ = 477/479/481 (chlorine isotope) 0.45 (silica gel, CH₂Cl₂/CH₃OH 95:5) 2.41 min 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-3-on-4-yl)- benzamide 52

Σ: 7.2% (M − H)⁻ = 431/433/435 (chlorine isotope) 0.70 (silica gel, CH₃COOC₂H₅/ CH₃OH 9:1) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3- on-4-yl)-benzamide 81

Σ: 2.9% (M + H)⁺ = 463/465/467 (chlorine isotope) 0.44 (silica gel, CH₃COOC₂H₅/ CH₃OH 95:5 + CH₃COOH) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide 97

Σ: 1.0% (M − H)⁻ = 506/508/510 (bromine and chlorine isotope) 2.36 min 3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(morpholin-3-on-4-yl)-benzamide

Example 22 N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid (prepared by synthesis sequence analogously to Example 30a, 2d and 21a), (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and NMM in DMF, then pouring into water, extracting with ethyl acetate, drying over sodium sulphate, evaporation i. vac. and purifying by chromatography on silica gel (eluting gradient: ethyl acetate/isopropanol/ethanol 9:1:0->9:0:1).

Yield: 99%

R_(f) value: 0.13 (silica gel; dichloromethane/isopropanol=19:1)

C₂₂H₂₃ClN₄O₄ (442.91)

Mass spectrum: (M+H)⁺=443/445 (chlorine isotope)

The following compounds were prepared analogously:

structural formula R_(f) value No. Name Yield mass peak(s) or R_(t) 23

76% (M + H)⁺ = 473/475 (chlorine isotope) 0.50 (silica gel, CH₂Cl₂/ C₂H₅OH 9:1) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-3-methyl-4-(morpholin-3-on- 4-yl)-benzamide 24

22% (M + H)⁺ = 429/431 (chlorine isotope) 0.22 (silica gel, CH₂Cl₂/ C₂H₅OH 9:1) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)- benzamide 49

quant. (M + H)⁺ = 412/414 (chlorine isotope) 0.60 (silica gel, CH₂Cl₂/ C₂H₅OH 9:1) N-[1-(5-chloro-1H-indol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Example 27 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(morpholin-3-on-4-yl)-benzamide

254 mg (1.15 mmol) 4-(morpholin-3-on-4-yl)-benzoic acid (prepared by synthesis sequence analogously to Example 30a, 2d and 21a) are placed in 5 ml DMF and 428 mg (1.0 mmol) PfTU and 514 μl (3.0 mmol) DIPEA are added. After stirring at ambient temperature for 10 minutes 232 mg (1.0 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine-hydrochloride are added and the mixture is stirred for 16 hours at ambient temperature. Then the reaction mixture is filtered through basic aluminium oxide and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/methanol 100:0->90:10), the corresponding fractions are evaporated down i. vac., the residue is dissolved in acetonitrile/water and lyophilised.

Yield: 77%

C₂₀H₁₉ClN₄O₃ (398.85)

Mass spectrum: (M+H)⁺=399/401 (chlorine isotope)

The following compound is prepared analogously:

structural formula mass No. Name Yield peak(s) 28

80% (M + H)⁺ = 413/415 (chlorine isotope) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)- benzamide

Example 29

N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzamide

(a) 4-fluoro-3-methyl-benzoic acid chloride

14.00 g (90.8 mmol) 4-fluoro-3-methyl-benzoic acid are refluxed for 1 hour together with 50 ml of thionyl chloride and then evaporated down i. vac. The residue is further reacted without any more purification.

Yield: 15.70 g (quantitative)

C₈H₈ClFO (172.59)

(b) 4-fluoro-3-methyl-benzamide

15.70 g (91.0 mmol) 4-fluoro-3-methyl-benzoic acid chloride dissolved in 30 ml THF are added dropwise to 300 ml of conc. ammonia solution and then stirred for 2 hours at ambient temperature. The precipitate formed is filtered off, washed with water and dried.

Yield: 10.00 g (72%)

C₈H₈FNO (153.16)

R_(f) value: 0.31 (aluminium oxide; dichloromethane/methanol=50:1)

(c) 4-fluoro-3-methyl-benzonitrile

10.00 g (65.29 mmol) 4-fluoro-3-methyl-benzoic acid amide are stirred together with 50 ml phosphorus oxychloride for 4 hours at 60° C. and then evaporated down i. vac. The residue is poured into ice water, the resulting precipitate is filtered off and washed with water. After being taken up in ethyl acetate the organic phase is washed with sat. potassium carbonate solution, dried over sodium sulphate and evaporated down completely i. vac.

Yield: 8.00 g (91%)

C₈H₆FN (135.14)

R_(f) value: 0.84 (silica gel; dichloromethane)

(d) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzonitrile

7.00 g (51.8 mmol) 4-fluoro-3-methyl-benzonitrile are heated to 110° C. together with 1-N-methyl-[1,4]diazepan for 1 week with stirring. After evaporation i. vac. the residue is separated on aluminium oxide (eluant: dichloromethane) and the corresponding fractions are again purified on silica gel (eluting gradient: dichloromethane/methanol 100:1->9:1).

Yield: 1.70 g (14%)

C₁₄H₁₉N₃ (229.33)

Mass spectrum: (M+H)⁺=230

R_(f) value: 0.25 (silica gel; dichloromethane/methanol=9:1)

(e) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid

Prepared analogously to Example 1b from 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzonitrile with 25% potassium hydroxide solution by refluxing for 36 hours. After evaporation i. vac. the residue is separated on aluminium oxide (eluant: dichloromethane) and the corresponding fractions are again purified on silica gel (eluting gradient: dichloromethane/methanol 100:1->9:1).

Yield: 14%

C₁₄H₁₉N₂O₂ (248.33)

Mass spectrum: (M+H)⁺=249

R_(f) value: 0.30 (RP-18; methanol/5% aqueous sodium chloride solution=6:4)

(f) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid chloride

Prepared analogously to Example 29a from 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid and thionyl chloride.

Yield: quantitative

C₁₄H₁₉ClN₂O.HCl (266.77/303.23)

(g) N-[1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzamide

489 mg (1.61 mmol) 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid chloride are placed together with 400 mg (3.96 mmol) TEA in 10 ml THF at ambient temperature and a solution of 433 mg (1.61 mmol) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl amine is added dropwise with stirring. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is combined with water and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on aluminium oxide (eluant: dichloromethane/methanol 100:1). The fractions evaporated down are treated with ethereal hydrochloric acid, after total concentration evaporated twice with ethyl acetate and diethyl ether and dried i. vac. at 70° C.

Yield: 120 mg (16%)

C₂₃H₂₈ClN₅O.HCl (462.43/425.96)

Mass spectrum: (M+H)⁺=426/428 (chlorine isotope)

R_(f) value: 0.47 (aluminium oxide; dichloromethane/methanol 19:1)

Example 30 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide

(a) methyl 4-(N-Boc-piperazin-1-yl)-3-methyl-benzoate

4.00 g (17.5 mmol) 4-bromo-3-methyl-benzoate methyl are suspended together with 3.92 g (21.0 mmol) N-Boc-piperazine, 39.2 mg (175 μmol) palladium (II)acetate, 50.7 mg (175 μmol) tri-tert.-butyl-phosphonium-tetrafluoroborate and 11.12 g (52.4 mmol) potassium phosphate in 35 ml of toluene and under an argon atmosphere heated to 150° C. for 10 minutes in a microwave oven. Then the reaction mixture is poured into water, stirred vigorously and extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate, applied to silica gel and purified by chromatography on silica gel (eluant: dichloromethane/methanol 80:1).

Yield: 1.42 g (24%)

C₁₈H₂₆N₂O₄ (334.42)

Mass spectrum: (M+H)⁺=335

R_(f) value: 0.52 (silica gel; dichloromethane/methanol=50:1)

(b) 4-(N-Boc-piperazin-1-yl)-3-methyl-benzoic acid

1.42 g (4.24 mmol) of methyl 4-(N-Boc-piperazin-1-yl)-3-methyl-benzoate are dissolved in 7 ml THF and 9.25 ml of water and 893 mg (21.3 mmol) lithium hydroxide-monohydrate are added. After stirring for 16 hours at ambient temperature the mixture is heated to 45° C. for 2 hours. Then another 893 mg (21.3 mmol) lithium hydroxide monohydrate are added and the mixture is stirred for 4 days at ambient temperature. Then it is neutralised with 1-molar hydrochloric acid and the reaction mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down completely i. vac.

Yield: 1.29 g (95%)

C₁₇H₂₄N₂O₄ (320.39)

Mass spectrum: (M+H)⁺=321

R_(f) value: 0.29 (silica gel; dichloromethane/methanol=15:1)

(c) 4-(N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl)-3-methyl-benzamide

Prepared analogously to Example 1f from 4-(N-Boc-piperazin-1-yl)-3-methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then stirring into conc. sodium hydrogen carbonate solution, extraction with ethyl acetate, drying over sodium sulphate, evaporation i. vac. and purification of the residue by chromatography on silica gel (eluting gradient: dichloromethane/methanol 50:1->15:1).

Yield: 85%

R_(f) value: 0.15 (silica gel; dichloromethane/methanol=30:1)

C₂₆H₃₂ClN₅O₃ (498.03)

Mass spectrum: (M+H)⁺=498/500 (chlorine isotope)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide

Prepared analogously to Example 1g from 4-(N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl)-3-methyl-benzamide and TFA in dichloromethane.

Yield: quantitative

C₂₁H₂₄ClN₅O (397.91)

Mass spectrum: (M+H)⁺=398/400 (chlorine isotope)

R_(f) value: 0.14 (silica gel; dichloromethane/methanol=9:1)

The following compound is prepared analogously:

structural formula R_(f) value No. Name Yield mass peak(s) or R_(t) 65

Σ: 5.9% (M + H)⁺ = 428/430 (chlorine isotope) 0.11 (silica gel, CH₂Cl₂/ CH₃OH 9:1) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperazin-1-yl)-benzamide

Example 31 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-2-on-1-yl)-benzamide

(a) methyl 4-(N-Boc-piperazin-2-on-1-yl)-3-methyl-benzoate

758 mg (3.31 mmol) methyl 4-bromo-3-methyl-benzoate are suspended together with 796 mg (21.0 mmol) 4-N-Boc-piperazin-2-one, 31.8 mg (167 μmol) copper (I)iodide, 35.1 μl (330 μmol) N,N′-dimethyl-ethylenediamine and 0.92 g (6.62 mmol) potassium carbonate in 6.6 ml of toluene and under an argon atmosphere heated to 140° C. in a microwave oven with stirring for 1.5 hours. Then the reaction mixture is poured into water, stirred vigorously and extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate, applied to silica gel and purified by chromatography on silica gel (eluant: dichloromethane/methanol 50:1).

Yield: 679 mg (59%)

C₁₈H₂₄N₂O₅ (348.40)

Mass spectrum: (M+H)⁺=349

R_(f) value: 0.25 (silica gel; dichloromethane/methanol=50:1)

(b) 4-(N-Boc-piperazin-2-on-1-yl)-3-methyl-benzoic acid

775 mg (2.22 mmol) methyl 4-(N-Boc-piperazin-2-on-1-yl)-3-methyl-benzoate are dissolved in 3.7 ml THF and 4.9 ml of water as well as 468 mg (11.2 mmol) lithium hydroxide-monohydrate are added. After stirring for 16 hours at ambient temperature the mixture is neutralised with 1-molar hydrochloric acid and the reaction mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down completely i. vac.

Yield: 664 mg (89%)

C₁₇H₂₂N₂O₅ (334.38)

Mass spectrum: (M+H)⁺=335

R_(f) value: 0.31 (silica gel; dichloromethane/methanol=15:1)

(c) 4-(N-Boc-piperazin-2-on-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl)-3-methyl-benzamide

Prepared analogously to Example 1f from 4-(N-Boc-piperazin-1-yl)-3-methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then stirring into conc. sodium hydrogen carbonate solution, extraction with ethyl acetate, drying over sodium sulphate, evaporation i. vac. and purification of the residue by chromatography on silica gel (eluant: dichloromethane/methanol 30:1).

Yield: 71%

R_(f) value: 0.30 (silica gel; dichloromethane/methanol=15:1)

C₂₆H₃₀ClN₅O₄ (512.01)

Mass spectrum: (M+H)⁺=512/514 (chlorine isotope)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperazin-2-on-1-yl)-benzamide

Prepared analogously to Example 1g from 4-(N-Boc-piperazin-1-yl)-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-benzamide and TFA in dichloromethane.

Yield: 36%

C₂₁H₂₂ClN₅O₂ (411.90)

Mass spectrum: (M+H)⁺=412/414 (chlorine isotope)

R_(f) value: 0.42 (silica gel; dichloromethane/methanol=9:1)

The following compounds were prepared analogously:

structural formula R_(f) value No. Name Yield mass peak(s) or R_(t) 66

Σ: 17% (M + H)⁺ = 442/444 (chlorine isotope) 0.18 (silica gel, CH₂Cl₂/ CH₃OH 9:1) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperazin-2-on-1-yl)-benzamide 98

Σ: 0.11% (M + H)⁺ = 426/428 (chlorine isotope) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(7-oxo-[1,4]diazepan-1-yl)-benzamide

Example 32 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide

(a) methyl 3-methyl-4-(piperidin-2-on-1-yl)-benzoate

Prepared analogously to Example 31a from methyl 4-bromo-3-methyl-benzoate and piperidin-2-one in the presence of copper (I)iodide, N,N′-dimethyl-ethylenediamine and potassium carbonate in toluene and dioxane under an argon atmosphere.

Yield: 34%

C₁₄H₁₇NO₃ (247.30)

Mass spectrum: (M+H)⁺=248

R_(f) value: 0.21 (silica gel; petroleum ether/ethyl acetate=1:1)

(b) 3-methyl-4-(piperidin-2-on-1-yl)-benzoic acid

Prepared analogously to Example 2d from methyl 3-methyl-4-(piperidin-2-on-1-yl)-benzoate and 1-molar sodium hydroxide solution in methanol.

Yield: 83%

C₁₃H₁₅NO₃ (233.27)

Mass spectrum: (M+H)⁺=234

R_(f) value: 0.51 (silica gel; ethyl acetate/ethanol=9:1+1% conc. ammonia solution)

(c) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl)-3-methyl-4-(piperidin-2-on-1-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(piperidin-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then stirring into ice water, combining with ammonia solution, filtering, taking up in dichloromethane, evaporation i. vac. and purification of the residue by chromatography on silica gel (eluting gradient: ethyl acetate/(methanol/conc. ammonia solution 19:1) 1:0->9:1).

Yield: 32%

R_(f) value: 0.30 (silica gel; ethyl acetate/ethanol=9:1+1% acetic acid)

C₂₂H₂₃ClN₄O₂ (410.91)

Mass spectrum: (M+H)⁺=411/413 (chlorine isotope)

The following compounds were prepared analogously:

structural formula No. Name Yield mass peak(s) R_(f) value or R_(t) 55

Σ: 4.5% (M + H)⁺ = 429/431 (chlorine isotope) 0.40 (silica gel, CH₃COOC₂H₅/ C₂H₅OH 19:1 + 1% NH₃) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide 56

Σ: 16% (M + H)⁺ = 441/443 (chlorine isotope) 0.30 (silica gel, CH₃COOC₂H₅/ C₂H₅OH 9:1 + 1% NH₃) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(piperidin-2-on-1-yl)-benzamide 80

Σ: 8.0% (M + H)⁺ = 459/461 (chlorine isotope) 0.60 (silica gel, CH₃COOC₂H₅/ C₂H₅OH 9:1 + 1% NH₃) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)- benzamide

Example 33 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(N-methyl-piperazin-1-yl)-3-trifluoromethyl-benzamide

170 mg (0.24 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperazin-1-yl)-3-trifluoromethyl-benzamide are suspended in 2 ml 1,2-dichloroethane and under a nitrogen atmosphere combined with 20 mg (0.67 mmol) paraformaldehyde and 76 mg (0.36 mmol) sodium triacetoxyborohydride. After the addition of 5 ml THF the reaction mixture is stirred for 6 hours at ambient temperature, then 100 mg (3.33 mmol) of paraformaldehyde and 100 mg (0.47 mmol) sodium triacetoxyborohydride are added and the mixture is stirred for a further 22 hours at ambient temperature. Then it is combined with sat. sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate, evaporated down i. vac. and purified by chromatography on silica gel (eluting gradient: dichloromethane/(methanol/conc. ammonia solution 19:1) 100:0->92:8).

Yield: 70 mg (59%)

C₂₃H₂₅ClF₃N₅O₂ (495.94)

Mass spectrum: (M+H)⁺=496/498 (chlorine isotope)

R_(f) value: 0.25 (silica gel; dichloromethane/methanol=9:1+1% conc. ammonia solution)

Example 34 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphonyl-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

150 mg (0.32 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-prop-1-yl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide are dissolved in a mixture of 10 ml dichloromethane and 1 ml acetic acid at −15° C. and combined with 204 mg (0.89 mmol) 3-chloroperbenzoic acid. The mixture is then stirred for 30 minutes at −15 to −10° C., heated to ambient temperature and stirred for a further 16 hours. Then the reaction mixture is washed twice with 5% sodium hydrogen carbonate solution, dried over sodium sulphate, evaporated down i. vac. and purified by chromatography on silica gel (eluant: dichloromethane/ethanol 95:5).

Yield: 80 mg (50%)

C₂₃H₂₅ClN₄O₅S (505.00)

Mass spectrum: (M+H)⁺=505/507 (chlorine isotope)

R_(f) value: 0.45 (silica gel; dichloromethane/ethanol=9:1)

Example 35

N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(pyrrolidin-2-on-1-yl)-benzamide

Prepared analogously to Example 27 from 4-(pyrrolidin-2-on-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propylamine, PfTU and TEA in DMSO at ambient temperature and subsequent Boc cleaving with TFA analogously to Example 1g.

HPLC-MS results:

retention time: 3.69 min

C₂₂H₂₃ClN₄O₂S (442.97)

Mass spectrum: (M+H)⁺=443/445 (chlorine isotope)

The following compound is prepared analogously:

structural formula mass peak(s) retention time No. Name 36

(M + H)⁺ = 445/447 (chlorine isotope) 3.80 min N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-4-(pyrrolidin-2-on- 1-yl)-benzamide

Example 39 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide

(a) methyl 4-isocyanato-3-methyl-benzoate

1.50 g (9.08 mmol) methyl 4-amino-3-methyl-benzoate are dissolved in 250 ml dioxane combined with 1.3 ml (10.7 mmol) trichloromethyl-chloroformate and refluxed for 5.5 hours with stirring. Then the mixture is evaporated down i. vac. and the residue is further reacted without any more purification.

Yield: 1.74 g (quantitative)

C₁₀H₉NO₃ (191.19)

(b) methyl 4-(N-[4-chlorobutoxycarbonyl]amino)-3-methyl-benzoate

1.74 g (9.08 mmol) 4 methyl-isocyanato-3-methyl-benzoate dissolved in 100 ml of toluene are combined with 1.07 ml (9.11 mmol) 85% m 4-chloro-butan-1-ol. The mixture is refluxed for 17 hours with stirring. After evaporation i. vac. the residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 17:3->17:4).

Yield: 1.19 g (44%)

C₁₄H₁₈ClNO₄ (299.76)

Mass spectrum: (M−H)⁻=298/300 (chlorine isotope)

R_(f) value: 0.45 (silica gel; petroleum ether/ethyl acetate=80:20)

(c) methyl 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoate

300 mg (1.00 mmol) methyl 4-(N-[4-chlorobutoxycarbonyl]-amino)-3-methyl-benzoate are dissolved in 10 ml DMF combined with 168 mg (1.50 mmol) potassium-tert.-butoxide and stirred for 3 hours at 60° C. The reaction mixture is mixed with water and extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. Then the residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 3:2).

Yield: 160 mg (61%)

R_(f) value: 0.26 (silica gel; petroleum ether/ethyl acetate 3:2)

C₁₄H₁₇NO₄ (263.30)

Mass spectrum: (M+H)⁺=264

(d) 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoic acid

150 mg (0.57 mmol) methyl 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoate are suspended in 1 ml of ethanol and combined with 0.26 ml (0.87 mmol) 8% aqueous lithium hydroxide solution. The mixture is stirred for 3 hours at ambient temperature and then evaporated down i. vac. The aqueous residue is extracted twice with ethyl acetate, then acidified and extracted twice more with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.

Yield: 122 mg (86%)

C₁₃H₁₅NO₄ (249.27)

Mass spectrum: (M+H)⁺=250

R_(f) value: 0.14 (silica gel; dichloromethane/methanol=95:5)

(e) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then acidifying with TFA and purification of the residue by chromatography (preparative HPLC).

Yield: 54%

C₂₂H₂₃ClN₄O₃.2CF₃COOH (654.96/426.90)

Mass spectrum: (M+H)⁺=427/429 (chlorine isotope)

R_(t): 2.42 min

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(t) No. Name 43

Σ: 12% (M − H)⁻ = 455/457 (chlorine isotope) 2.43 min N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- ([1,3]oxazepan-2-on-3-yl)-benzamide 51

Σ: 2.6% (M − H)⁻ = 397/399 (chlorine isotope) 3.70 min N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(oxazolidin-2- on-3-yl)-benzamide 57

Σ: 3.4% (M + H)⁺ = 413/415 (chlorine isotope) 3.63 min N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]- oxazinan-2-on-3-yl)-benzamide 58

Σ: 2.7% (M + H)⁺ = 443/445 (chlorine isotope) 3.66 min N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- ([1,3]-oxazinan-2-on-3-yl)-benzamide 68

Σ: 0.32% (M + H)⁺ = 511/513 (chlorine isotope) 4.21 min N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- ([1,3]oxazepan-2-on-3-yl)-3-trifluoromethyl-benzamide

Example 41 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide

(a) methyl 4-(morpholin-3-on-4-yl)-3-nitro-benzoate

1.00 g (3.85 mmol) methyl 4-bromo-3-nitro-benzoate are dissolved in 6 ml dioxane with 389 mg (3.85 mmol) morpholin-3-one under a nitrogen atmosphere and 36.6 mg (40 μmol) tris-(dibenzylideneacetone)-dipalladium (0), 67.1 mg (116 μmol) xantphos and 1.75 g (5.38 mmol) caesium carbonate are added. Under a nitrogen atmosphere and with stirring, the reaction mixture is heated to 95° C. for 16 hours. Then it is filtered, the solution is evaporated down i. vac. and evaporated with ether. The residue is further reacted without any more purification. Yield: 1.31 g (quantitative)

C₁₂H₁₂N₂O₆ (280.24)

Mass spectrum: (M+H)⁺=281

R_(f) value: 0.47 (Reversed phase 8; methanol/5% sodium chloride solution=6:4)

(b) 4-(2-carboxymethoxy-ethylamino)-3-nitro-benzoic acid

400 mg (1.43 mmol) methyl 4-(morpholin-3-on-4-yl)-3-nitro-benzoate are dissolved in 15 ml of methanol and combined with 4.5 ml (4.5 mmol) 1-molar lithium hydroxide solution. The mixture is stirred for 2 hours at ambient temperature. Then it is evaporated down i. vac., the residue is diluted with water, cooled in the ice bath and acidified with 2-molar hydrochloric acid. After 10 minutes cooling in the ice bath the precipitate formed is filtered off, washed with water until neutral and dried at 50° C. in the drying cupboard.

Yield: 290 mg (72%)

C₁₁H₁₂N₂O₇ (284.23)

Mass spectrum: M⁺=284

R_(f) value: 0.59 (Reversed phase 8; methanol/5% sodium chloride solution=6:4)

(c) 4-(morpholin-3-on-4-yl)-3-nitro-benzoic acid-chloride

290 mg (1.02 mmol) 4-(2-carboxymethoxy-ethylamino)-3-nitro-benzoic acid in 100 ml dichloromethane are combined with 0.186 ml (2.55 mmol) thionyl chloride and 2 drops of DMF and refluxed for one day. After evaporation of the solution i. vac. it is evaporated with toluene and the residue is further reacted without any more purification.

Yield: 290 mg (quant.)

C₁₁H₉ClN₂O₅ (284.66)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide

237 mg (0.93 mmol) of (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propylamine are dissolved with 0.257 ml TEA in 10 ml THF and a solution of 290 mg (1.02 mmol) 4-(morpholin-3-on-4-yl)-3-nitro-benzoic acid chloride in 10 ml THF is added dropwise. The reaction mixture is stirred for 16 hours at ambient temperature and then evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0->95:5).

Yield: 34%

C₂₂H₂₂ClN₅O₅S (503.97)

Mass spectrum: (M−H)⁻=502/504 (chlorine isotope)

R_(f) value: 0.46 (silica gel; dichloromethane/ethanol=9:1)

Example 42 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide

(a) 4-(3-Boc-amino-propyl-amino)-3-chloro-benzonitrile

3.49 g (20 mmol) 3-Boc-amino-propylamine in 5 ml DMF are combined with 2.75 ml (25 mmol) NMM. After the addition of 3.11 g (20 mmol) 3-chloro-4-fluoro-benzonitrile the mixture is stirred for 3.5 hours at ambient temperature under a nitrogen atmosphere, heated to 105° C. for 20 minutes and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac. The residue is further reacted without any more purification.

Yield: 5.50 g (89%)

C₁₅H₂₀N₃O₂ (309.80)

Mass spectrum: (M+H)⁺=310/312 (chlorine isotope)

R_(f) value: 0.40 (silica gel; petroleum ether/ethyl acetate=2:1)

(b) 4-(3-amino-propylamino)-3-chloro-benzonitrile

4.50 g (14.5 mmol) 4-(3-Boc-amino-propylamino)-3-chloro-benzonitrile are dissolved in 50 ml dioxane and combined with 200 ml 6-molar hydrochloric acid. The mixture is stirred for 2 hours at ambient temperature, then washed with ether and the aqueous phase is poured into 125 ml ice-cooled conc. ammonia solution. Then the mixture is extracted with ethyl acetate, the combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac. The residue is further reacted without any more purification.

Yield: 1.40 g (46%)

C₁₀H₁₂ClN₃ (209.68)

Mass spectrum: (M+H)⁺=210/212 (chlorine isotope)

R_(f) value: 0.30 (silica gel; dichloromethane/methanol=9:1+1% conc. ammonia solution)

(c) 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzonitrile

A solution of 349 mg (2.15 mmol) N,N′-carbonyl-diimidazole in 3 ml NMP is combined with 450 mg (2.15 mmol) 4-(3-amino-propylamino)-3-chloro-benzonitrile at ambient temperature with stirring and once fully dissolved heated for one hour to 145° C. and for 1.5 hours to 155° C. The reaction mixture is washed with water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac. Then the residue is purified by chromatography on silica gel (eluting gradient: ethyl acetate/(methanol/conc. ammonia solution 19:1)=100:0->95:5).

Yield: 260 mg (51%)

R_(f) value: 0.40 (silica gel; ethyl acetate/ethanol 9:1+1% conc. ammonia solution)

C₁₁H₁₀ClN₃O (235.68)

Mass spectrum: (M+H)⁺=236/238 (chlorine isotope)

(d) 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzoic acid

350 mg (1.49 mmol) 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzonitrile are suspended in 5 ml of ethanol and combined with 2.0 ml of 10-molar aqueous sodium hydroxide solution. The mixture is stirred for one hour at 100° C. and then evaporated down i. vac. The aqueous residue is combined with ice, acidified with acetic acid and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac. The aqueous phase is acidified with 6-molar hydrochloric acid, extracted 5 times with ethyl acetate, the combined organic phases are washed with sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac.

Yield: 340 mg (90%)

C₁₁H₁₁ClN₂O₃ (254.68)

Mass spectrum: (M+H)⁺=255/257 (chlorine isotope)

R_(f) value: 0.35 (silica gel; dichloromethane/methanol=9:1+1% acetic acid)

(e) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzamide

Prepared analogously to Example 1f from 3-chloro-4-(tetrahydro-pyrimidin-2-on-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF, then pouring into ice water, adding conc. ammonia solution, filtering, washing with water and purifying by chromatography on silica gel (eluting gradient ethyl acetate/(methanol/conc. ammonia solution 19:1)=98:2->90:10) with subsequent filtration through activated charcoal, trituration with ether and drying in the drying pistol at 70° C.

Yield: 32%

C₂₀H₁₉Cl₂N₅O₂ (432.31)

Mass spectrum: (M+H)⁺=432/434/436 (chlorine isotope)

R_(f) value: 0.40 (silica gel; dichloromethane/methanol=9:1+1% acetic acid)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 114

Σ: 5.4% (M + H)⁺ = 462/464/466 (chlorine isotope) 0.52 (ethyl acetate/ ethanol = 8:2) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (tetrahydro-pyrimidin-2-on-1-yl)-benzamide

Example 46 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide

(a) methyl 3-chloro-4-(5-chloro-pentanoyl-amino)-benzoate

A solution of 696 μl (0.84 g, 5.39 mmol) 5-chloro-pentanoylchloride in 10 ml THF is slowly added dropwise to 1.00 g (5.39 mmol) methyl 4-amino-3-chloro-benzoate in 20 ml THF with 1 ml TEA with stirring in the ice bath. After stirring for 16 hours at ambient temperature, for 3 hours at 50° C. and for 3 hours at reflux temperature the mixture is poured into water and extracted with ethyl acetate. After the organic phases have been dried over sodium sulphate the mixture is evaporated down i. vac. and the residue remaining is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 85:15).

Yield: 300 mg (14.6%) 80% product

C₁₃H₁₅Cl₂NO₃ (304.18)

Mass spectrum: (M+H)⁺=304/306/308 (chlorine isotope)

R_(t) value: 3.29 min

(b) methyl 3-chloro-4-(piperidin-2-on-1-yl)-benzoate

300 mg (0.79 mmol) of the product obtained in Example 46a is dissolved in 10 ml DMF and combined with 180 mg (1.60 mmol) potassium-tert.-butoxide and heated to 60° C. for 3 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue obtained is purified by chromatography on silica gel (eluant: dichloromethane/isopropanol 98:2).

Yield: 159 mg (75%)

C₁₃H₁₄ClNO₃ (267.71)

Mass spectrum: (M+H)⁺=268/270 (chlorine isotope)

R_(f) value: 0.18 (silica gel; dichloromethane/isopropanol=49:1)

(c) 3-chloro-4-(piperidin-2-on-1-yl)-benzoic acid

Prepared analogously to Example 39d from methyl 3-chloro-4-(piperidin-2-on-1-yl)-benzoate and 8% lithium hydroxide solution in ethanol.

Yield: 36%

C₁₂H₁₂ClNO₃ (247.30)

Mass spectrum: (M+H)⁺=252/254 (chlorine isotope)

R_(f) value: 0.27 (silica gel; dichloromethane/ethanol=9:1)

(d) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2-on-1-yl)-benzamide

Prepared analogously to Example 1f from 3-chloro-4-(piperidin-2-on-1-yl)-benzoic acid, TBTU, NMM and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine in DMF and subsequent purification by chromatography on silica gel (eluting gradient: ethyl acetate/ethanol 95:5->90:10).

Yield: 70%

C₂₂H₂₂Cl₂N₄O₃ (461.35)

Mass spectrum: (M−H)⁻=459/461/463 (chlorine isotope)

R_(f) value: 0.19 (silica gel; dichloromethane/ethanol=19:1)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 59

Σ: 1.3% (M + H)⁺ = 495/497 (chlorine isotope) 2.51 min N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(piperidin-2- on-1-yl)-3-trifluoromethyl-benzamide

Example 47 N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-bromo-phenyl)-N-Boc-(S)-serinamide and N′-(2-amino-5-bromo-phenyl)-N-Boc-(S)-serinamide

5.49 g (26.7 mmol) (S)-N-Boc-serine are dissolved with 5.00 g (26.7 mmol) 4-bromo-1,2-phenylenediamine in 125 ml THF and a solution of 5.52 g (26.7 mmol) N,N′-dicyclohexylcarbodiimide in 20 ml THF is added dropwise while cooling with ice. The reaction mixture is stirred for 16 hours at ambient temperature. After evaporation i. vac. the residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol 98:2).

Yield: 4.76 g (48%) mixture of the two regioisomers

C₁₄H₂₀BrN₃O₄ (374.24)

Mass spectrum: (M+H)⁺=374/376 (bromine isotope)

(b) (1R)-N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine

3.00 g (8.02 mmol) of the mixture obtained in 47a are dissolved in 30 ml acetic acid and stirred for 2 hours at 50° C. The reaction mixture is added dropwise to a 10% sodium hydroxide solution and extracted 3 times with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down i. vac. and the residue is recrystallised from methanol.

Yield: 1.96 g (69%)

C₁₄H₁₈BrN₃O₃ (356.22)

R_(f) value: 0.59 (silica gel; petroleum ether/ethyl acetate=1:1)

(c) (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine

2.00 g (5.62 mmol) (1R)-N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine in 40 ml of ethyl acetate are combined with 8.0 ml 4-molar hydrochloric acid in dioxane while cooling in the ice bath and stirred for 16 hours at ambient temperature. The reaction mixture is evaporated down and the resulting precipitate is filtered off.

Yield: 1.11 g (67%)

C₉H₁₀BrN₃O.HCl (292.57/256.10)

Mass spectrum: (M+H)⁺=256/258 (bromine isotope)

(d) N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.

Yield: 52%

C₂₁H₂₁BrN₄O₄.CF₃COOH (587.35/473.32)

Mass spectrum: (M+H)⁺=473/475 (bromine isotope)

R_(f) value: 0.33 (silica gel; dichloromethane/methanol=19:1)

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 53

Σ: 6.6% (M + H)⁺ = 457/459 (chlorine isotope) 0.48 (silica gel, CH₂Cl₂/C₂H₅OH 9:1) N-[(1R,2S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-propyl]-3-methyl- 4-(morpholin-3-on-4-yl)-benzamide 62

Σ: 34% (M − H)⁻ = 441/443 (chlorine isotope) 0.40 (aluminium oxide, CH₂Cl₂/C₂H₅OH 19:1) 4-(azepan-2-on-1-yl)-N-[(1S)-1-(5-chloro-6-fluoro-1H-benzimidazol-2-yl)- ethyl]-3-methyl-benzamide 67

Σ: 38% (M + H)⁺ = 441/443 (chlorine isotope) 0.50 (silica gel, CH₂Cl₂/C₂H₅OH 9:1) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-butyl]-3-methyl-4-(morpholin-3- on-4-yl)-benzamide 78

Σ: 38% (M + H)⁺ = 481/483 (chlorine isotope) 0.51 (silica gel, CH₂Cl₂/C₂H₅OH 9:1) N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(thiophen-3-yl)-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide 79

Σ: 10.6% (M + H)⁺ = 459/461 (chlorine isotope) 0.50 (silica gel, CH₂Cl₂/C₂H₅OH 9:1) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylsulphanyl-ethyl]-3- methyl-4-(morpholin-3-on-4-yl)-benzamide 99

Σ: 18% (M + H)⁺ = 481/483 (chlorine isotope) 2.43 min N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(thiophen-2-yl)-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide 101

Σ: 2.9% (M + H)⁺ = 487/489 (bromine isotope) 2.31 min N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-4- ([1,3]oxazepan-2-on-3-yl)-benzamide

Example 48 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzamide

(a) methyl 4-(3-chloro-propyl-sulphonyl-amino)-3-methyl-benzoate

100 mg (0.61 mmol) methyl 4-amino-3-methyl-benzoate dissolved in 3 ml of pyridine are combined with 82 μl (0.67 mmol) 3-chloropropanesulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction solution is combined with water and ethyl acetate and then the aqueous phase is again extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is further reacted without any more purification.

Yield: 170 mg (92%)

C₁₂H₁₆ClNO₄S (305.78)

Mass spectrum: (M+H)⁺=306/308 (chlorine isotope)

R_(f) value: 0.10 (silica gel; petroleum ether/ethyl acetate=8:2)

(b) methyl 4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoate

370 mg (0.85 mmol) 70% methyl 4-(3-chloropropane-sulphonylamino)-3-methyl-benzoate dissolved in 26 ml DMF are combined with 275 mg (2.45 mmol) potassium-tert.-butoxide and stirred for 16 hours at ambient temperature. The reaction mixture is combined with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluant: dichloromethane/isopropanol 98:2).

Yield: 177 mg (47%)

C₁₂H₁₅NO₄S (269.32)

Mass spectrum: (M+H)⁺=270

R_(f) value: 0.10 (silica gel; petroleum ether/ethyl acetate=7:3)

(c) 4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoic acid

170 mg (0.63 mmol) methyl 4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoate are stirred in 2 ml of ethanol at ambient temperature for 3 hours with 0.6 ml of 2-molar sodium hydroxide solution. Then the reaction solution is evaporated down i. vac., combined with water and 0.6 ml 2-molar hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue is further reacted without any more purification.

Yield: 148 mg (92%)

C₁₁H₁₃NO₄S (255.30)

Mass spectrum: (M−H)⁻=254

retention time: 2.23 min

(d) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzamide

Prepared analogously to Example 1f from 4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF with subsequent extraction with ethyl acetate, drying over magnesium sulphate, activated charcoal and silica gel followed by purification on silica gel (eluant: dichloromethane/isopropanol 95:5).

Yield: 37%

C₂₀H₂₁ClN₄O₃S (432.93)

Mass spectrum: (M+H)⁺=433/435 (chlorine isotope)

R_(f) value: 0.32 (silica gel; dichloromethane/isopropanol=19:1)

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 60

Σ: 18% (M + H)⁺ = 477/479 (chlorine isotope) 2.46 min N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo- [1,2]thiazinan-2-yl)-3-methyl-benzamide 71

Σ: 20% (M + H)⁺ = 478/480 (chlorine isotope) 2.58 min N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo- [1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide 72

Σ: 19% (M + H)⁺ = 448/450 (chlorine isotope) 2.41 min N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo- [1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide 100

Σ: 2.5% (M + H)⁺ = 507/509 (bromine isotope) 2.38 min N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-4-(1,1-dioxo- [1,2]thiazinan-2-yl)-3-methyl-benzamide

Example 54 3-amino-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-benzamide

65 mg (0.13 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propyl]-4-(morpholin-3-on-4-yl)-3-nitro-benzamide dissolved in 2 ml of ethyl acetate are combined with 143 mg (0.63 mmol) tin (II)chloride-dihydrate and 130 mg (1.55 mmol) sodium hydrogen carbonate and refluxed for 2 hours. The reaction solution is combined with ice water, stirred for 10 minutes and then the precipitate formed is filtered off. After drying for 3 days the residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0->91:9).

Yield: 5 mg (8.2%)

C₂₂H₂₄ClN₅O₃S (473.99)

Mass spectrum: (M+H)⁺=474/476 (chlorine isotope)

R_(f) value: 0.48 (silica gel; dichloromethane/ethanol=9:1)

Example 61 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(5,6-didehydro-azepan-2-on-1-yl)-benzamide

(a) methyl 3-methyl-4-(pent-4-en-1-oyl-amino)-benzoate

Prepared analogously to Example 46a from methyl 4-amino-3-methyl-benzoate and 4-pentene-1-acid-chloride in THF with TEA.

Yield: 46%

C₁₄H₁₇NO₃ (247.30)

Mass spectrum: (M+H)⁺=248

R_(t) value: 2.88 min

(b) methyl 4-(allyl-pent-4-en-1-oyl-amino)-3-methyl-benzoate

1.00 g (4.04 mmol) methyl 3-methyl-4-(pent-4-en-1-oyl-amino)-benzoate dissolved in 5 ml DMF are combined with 500 mg (4.37 mmol) potassium-tert.-butoxide and at 40° C. 350 μl (489 mg, 4.04 mmol) allylbromide are slowly added with stirring. Then the mixture is heated to 70° C. for 3 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac., the residue is applied to silica gel and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1).

Yield: 58%

C₁₇H₂₁NO₃ (287.36)

Mass spectrum: (M+H)⁺=288

R_(f) value: 0.46 (petroleum ether/ethyl acetate=9:1)

(c) methyl 4-(4,5-didehydro-azepan-2-on-1-yl)-3-methyl-benzoate

150 mg (0.52 mmol) methyl 4-(allyl-pent-4-en-1-oyl-amino)-3-methyl-benzoate are dissolved in 110 ml degassed dichloromethane and rinsed for 30 minutes with argon. Then 88 mg (104 μmol) benzylidene-[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro-(tricyclohexylphosphine)-ruthenium (2nd generation Grubbs Catalyst) are added and the mixture is refluxed for 4.5 hours. Then it is evaporated down i. vac., the residue is applied to silica gel and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 3:2).

Yield: 83 mg (61%)

R_(f) value: 0.22 (silica gel, petroleum ether/ethyl acetate 3:2)

C₁₅H₁₇NO₃ (259.31)

Mass spectrum: (M+H)⁺=260

(d) 4-(4,5-didehydro-azepan-2-on-1-yl)-3-methyl-benzoic acid

Prepared analogously to Example 39d from methyl 4-(4,5-didehydro-azepan-2-on-1-yl)-3-methyl-benzoate and 8% lithium hydroxide solution in ethanol.

Yield: 51%

R_(f) value: 0.05 (silica gel; dichloromethane/methanol=19:1)

C₁₄H₁₅NO₃ (245.28)

Mass spectrum: (M+H)⁺=246

(e) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4,5-didehydro-azepan-2-on-1-yl)-3-methyl-benzamide

Prepared analogously to Example 1f from 4-(4,5-didehydro-azepan-2-on-1-yl)-3-methyl-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine in DMF and subsequent purification by preparative HPLC.

Yield: 32%

R_(f) value: 0.44 (silica gel; dichloromethane/methanol=19:1)

C₂₃H₂₃ClN₄O₂.CF₃COOH (536.94/422.91)

Mass spectrum: (M+H)⁺=423/425 (chlorine isotope)

Example 63 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,3-dioxo-thiomorpholin-4-yl)-3-methyl-benzamide

204 mg (0.48 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide are dissolved in a mixture of 12 ml dichloromethane and 1.2 ml acetic acid at −15° C. and combined with 110 mg (0.48 mmol) 3-chloroperbenzoic acid. The mixture is then stirred for one hour at −15 to −10° C., heated to ambient temperature and stirred for a further 3 hours. Then the reaction mixture is combined with semi-concentrated sodium hydrogen carbonate solution and extracted with a solvent mixture dichloromethane/methanol 19:1. The combined organic phases are washed with water, dried over magnesium sulphate, evaporated down i. vac. and purified by chromatography on silica gel (eluting gradient: ethyl acetate/(ethanol/conc. ammonia solution 19:1)=1:0->4:1).

Yield: 100 mg (47%)

C₂₁H₂₁ClN₄O₃S (444.94)

Mass spectrum: (M+H)⁺=445/447 (chlorine isotope)

R_(f) value: 0.15 (silica gel; ethyl acetate/ethanol=4:1+1% conc. ammonia solution)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value No. Name 64

Σ: 14% (M + H)⁺ = 461/463 (chlorine isotope) 0.70 (silica gel, CH₃COOC₂H₅/ C₂H₅OH 4:1 + 1% conc. ammonia solution) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(1,1,3-trioxo- thiomorpholin-4-yl)-benzamide

Example 69 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methoxy-4-(piperidin-2-on-1-yl)-benzamide

(a) methyl 4-(5-chloro-pentanoyl-amino)-3-methoxy-benzoate

Prepared analogously to Example 6a from methyl 4-amino-3-methoxy-benzoate and 5-chloro-pentanoic acid chloride in THF with TEA.

Yield: 99%

C₁₄H₁₈ClNO₄ (299.76)

Mass spectrum: (M+H)⁺=300/302 (chlorine isotope)

R_(t) value: 3.14 min

(b) methyl 3-methoxy-4-(piperidin-2-on-1-yl)-benzoate

2.25 g (7.51 mmol) methyl 4-(5-chloro-pentanoyl-amino)-3-methoxy-benzoate dissolved in 60 ml DMF are combined with 1.26 g (11.2 mmol) potassium-tert.-butoxide and stirred for 2.5 hours at 60° C. Then the mixture is evaporated down i. vac., the residue is combined with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue obtained is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate 3:2->0:1).

Yield: 0.99 g (50%)

R_(t) value: 2.56 min

C₁₄H₁₇NO₄ (263.30)

Mass spectrum: (M+H)⁺=264

(c) 3-methoxy-4-(piperidin-2-on-1-yl)-benzoic acid

Prepared analogously to Example 39d from methyl 3-methoxy-4-(piperidin-2-on-1-yl)-benzoate and lithium hydroxide in ethanol.

Yield: 95%

R_(t) value: 0.10 (silica gel; petroleum ether/ethyl acetate=1:2)

C₁₃H₁₅NO₄ (249.27)

Mass spectrum: (M+H)⁺=250

(d) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methoxy-4-(piperidin-2-on-1-yl)-benzamide

Prepared analogously to Example 1f from 3-methoxy-4-(piperidin-2-on-1-yl)-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in DMF and subsequent purification by preparative HPLC.

Yield: 75%

R_(t) value: 2.35 min

C₂₂H₂₃ClN₄O₃.CF₃COOH (540.93/426.90)

Mass spectrum: (M+H)⁺=427/429 (chlorine isotope)

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 70

Σ: 31% (M + H)⁺ = 457/459 (chlorine isotope) 2.31 min N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methoxy-4- (piperidin-2-on-1-yl)-benzamide 85

Σ: 0.8% (M + H)⁺ = 481/483 (chlorine isotope) 2.56 min N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2-on-1-yl)-3- trifluoromethoxy-benzamide 86

Σ: 6.2% (M + H)⁺ = 475/477/479 (bromine and chlorine isotope) 2.57 min 3-bromo-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(piperidin-2- on-1-yl)-benzamide 87

Σ: 6.2% (M + H)⁺ = 505/507/509 (bromine and chlorine isotope) 2.57 min 3-bromo-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (piperidin-2-on-1-yl)-benzamide

Example 73 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-6-methyl-[1,2,6]thia-diazinan-2-yl)-3-methyl-benzamide

(a) methyl 4-(1,1-dioxo-6-methyl-[1,2,6]-thiadiazinan-2-yl)-3-methyl-benzoate

400 mg (1.41 mmol) methyl 4-(1,1-dioxo-[1,2,6]-thiadiazinan-2-yl)-3-methyl-benzoate dissolved in 4 ml DMF at 40° C. are combined with 240 mg (2.14 mmol) potassium-tert.-butoxide and 96 μl (1.54 mmol) methyl iodide and stirred for 5 hours at 40° C. The reaction solution is evaporated down i. vac., combined with water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.

Yield: 220 mg (52%)

C₁₃H₁₈N₂O₄S (298.36)

Mass spectrum: (M+H)⁺=299

R_(f) value: 0.44 (silica gel; petroleum ether/ethyl acetate=3:2)

(b) 4-(1,1-dioxo-6-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzoic acid

Prepared analogously to Example 39d from methyl 4-(1,1-dioxo-3-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzoate and lithium hydroxide in ethanol.

Yield: (81%)

C₁₂H₁₆N₂O₄S (284.34)

Mass spectrum: (M+H)⁺=285

R_(f) value: 0.07 (silica gel; dichloromethane/methanol=19:1)

(c) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(1,1-dioxo-6-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide

Prepared analogously to Example 1f from 4-(1,1-dioxo-3-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.

Yield: 55%

C₂₁H₂₄ClN₅O₃S.CF₃COOH (576.00/461.97)

Mass spectrum: (M+H)⁺=462/464 (chlorine isotope)

R_(t) value: 2.50 min

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(t) value No. Name 74

Σ: 20% (M + H)⁺ = 492/494 (chlorine isotope) 2.56 min N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-6- methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzamide

Example 75 N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-bromo-phenyl)-N-Boc-(S)-O-methyl-serinamide and N′-(2-amino-5-bromo-phenyl)-N-Boc-(S)-O-methyl-serinamide

2.50 g (6.24 mmol) of the dicyclohexylammonium salt of N-Boc-(S)-O-methyl-serine are dissolved in 20 ml 5% citric acid, the aqueous phase is extracted 2× with 20 ml of ethyl acetate, the combined organic phases are dried over sodium sulphate and freed from solvent i. vac. The residue is dissolved together with 1.23 g (6.55 mmol) 4-bromo-1,2-phenylenediamine in 30 ml THF and 1.42 ml (14.0 mmol) triethylamine and 4.97 ml (7.80 mmol) of a 50% solution of PPA in ethyl acetate are added with stirring in the ice bath. After 5 minutes stirring in the ice bath the mixture is heated to ambient temperature and stirred for 23 hours at ambient temperature. The reaction mixture is poured into 100 ml of water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are extracted with sat. sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac.

Yield: 2.38 g (98%) mixture of the two regioisomers

C₁₅H₂₂BrN₃O₄ (388.26)

Mass spectrum: (M+H)⁺=388/390 (bromine isotope)

R_(f) value: 0.63/0.68 (silica gel; dichloromethane/ethanol=9:1)

(b) (1R)-N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethylamine

2.38 g (6.13 mmol) of the mixture obtained in 75a are dissolved in 150 ml of toluene and 1.84 ml (30.7 mmol) acetic acid and 4.00 g molecular sieve, 3A, are added. The reaction mixture is stirred for 3 hours at 55° C. and then cooled for 15 minutes in the ice bath. The reaction mixture is filtered and poured into a mixture of 500 ml each of water and ethyl acetate. After vigorous mixing the organic phase is separated off, washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol 100:0->97:3).

Yield: 1.40 g (62%)

C₁₅H₂₀BrN₃O₃ (370.24)

Mass spectrum: (M+H)⁺=370/372 (bromine isotope)

R_(f) value: 0.81 (silica gel; dichloromethane/ethanol=9:1)

(c) (1R)-1-(5-bromo-1H-benzimidazole-1-yl)-2-methoxy-ethylamine

Prepared analogously to Example 1g from (1R)-N-Boc-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethylamine and TFA in dichloromethane.

Yield: 51%

C₁₀H₁₂BrN₃O (270.13)

Mass spectrum: (M+H)⁺=270/272 (bromine isotope)

R_(f) value: 0.20 (silica gel, dichloromethane/ethanol 9:1)

(d) N-[(1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.

Yield: quant.

C₂₂H₂₃BrN₄O₄ (487.35)

Mass spectrum: (M+H)⁺=487/489 (bromine isotope)

R_(f) value: 0.56 (silica gel; dichloromethane/ethanol=9:1)

Example 76 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butyrate

5.00 g (11.3 mmol) dicyclohexylammonium-(2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butanoate are stirred into in 100 ml of 5% citric acid solution and then extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and the solvent is distilled off i. vac. The residue is dissolved in 70 ml THF, 4.35 g (13.5 mmol) TBTU and 6.35 ml (33.8 mmol) DIPEA are added and the mixture is stirred for 10 minutes at ambient temperature. Then 50 ml of ethanol are added and the mixture is refluxed for 16 hours. Then the reaction mixture is evaporated down i. vac., taken up in ethyl acetate, washed with semisaturated sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated down i. vac.

Yield: 3.20 g (98%)

C₁₅H₁₈N₂O₄ (290.32)

Mass spectrum: (M+NH₄)⁺=308

R_(f) value: 0.80 (silica gel; dichloromethane/ethanol=9:1)

(b) ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyrate

3.20 g (11.0 mmol) ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-cyano-butyrate are dissolved in 40 ml of toluene and 1.08 g (16.5 mmol) sodium azide and 2.28 g (16.5 mmol) triethylamine-hydrochloride are added. The reaction mixture is heated to 85° C. for 24 hours, cooled to ambient temperature and extracted with water. The combined aqueous phases are acidified to pH 2 with semiconc. hydrochloric acid, the resulting precipitate is suction filtered, washed with water and dried at 50° C.

Yield: 2.90 g (79%)

C₁₅H₁₉N₅O₄ (333.34)

Mass spectrum: (M+H)⁺=334

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=9:1)

(c) (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyric acid

Prepared analogously to Example 30b from ethyl (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyrate and lithium hydroxide in a mixture of solvents from water and THF.

Yield: quant.

C₁₃H₁₅N₅O₄ (305.29)

Mass spectrum: (M+H)⁺=306

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=4:1)

(d) N′-(2-amino-4-chloro-phenyl)-(2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyric acid amide and N′-(2-amino-5-chloro-phenyl)-(2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyric acid amide

Prepared analogously to Example 47a from (2S)-2-(benzyloxycarbonyl-amino)-4-(1H-tetrazol-5-yl)-butyric acid and 4-chloro-1,2-phenylenediamine with DCC in THF.

Yield: quant., mixture of the two regioisomers, slightly contaminated

C₁₉H₂₀ClN₇O₃ (429.86)

R_(f) value: 0.20 (silica gel; dichloromethane/ethanol=9:1)

(e) (1S)-N-(benzyloxycarbonyl)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine

Prepared analogously to Example 47b from the product obtained in Example 76d and acetic acid.

Yield: quant.

C₁₃H₁₈ClN₇O₂.CH₃COOH (471.90/411.85)

R_(f) value: 0.25 (silica gel; dichloromethane/ethanol/conc. ammonia=4:1:0.1)

(f) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine

2.10 g (4.45 mmol) (1S)-N-(benzyloxycarbonyl)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine in 30 ml dichloromethane are combined with 1.9 ml (13.4 mmol) iodo-trimethylsilane and stirred for 16 hours at ambient temperature. Then 20 ml of methanol are added, the mixture is stirred for a further 30 minutes at ambient temperature and the reaction mixture is evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/(ethanol/conc. ammonia 95:5)=70/30->60:40).

Yield: 690 mg (56%)

C₁₁H₁₂ClN₇ (277.71)

Mass spectrum: (M+H)⁺=278/280 (chlorine isotope)

R_(f) value: 0.15 (silica gel; dichloromethane/ethanol=3:2+1% conc. ammonia)

(g) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.

Yield: 33%

C₂₃H₂₃ClN₈O₃ (494.93)

Mass spectrum: (M+H)⁺=495/497 (chlorine isotope)

R_(f) value: 0.20 (silica gel; dichloromethane/ethanol=4:1)

Example 77 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-chloro-phenyl)-(2S)-2-(Boc-amino)-3-methoxy-propionic acid amide and N′-(2-amino-5-chloro-phenyl)-(2S)-2-(Boc-amino)-3-methoxy-propionic acid amide

4.90 g (21.0 mmol) (2S)-2-(Boc-amino)-3-methoxy-propionic acid are dissolved in 20 ml THF and combined with 13.57 g (42.0 mmol) TBTU and 5.76 ml (52.5 mmol) triethylamine and stirred for 30 minutes at ambient temperature. Then 3.00 g (21.0 mmol) 4-chloro-1,2-phenylenediamine in 20 ml THF are added and the mixture is stirred for 16 hours at ambient temperature. Then the reaction mixture is evaporated down i. vac., poured into water and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol 99:1).

Yield: 5.60 g (75%) mixture of the two regioisomers

C₁₆H₂₄ClN₃O₃ (357.83)

Mass spectrum: (M+H)⁺=358/360 (chlorine isotope)

R_(f) value: 0.26 (silica gel; dichloromethane/methanol=99:1)

(b) (1S)-N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine

Prepared analogously to Example 47b from the product obtained in Example 77a and acetic acid.

Yield: 96%

C₁₆H₂₂ClN₃O₃ (339.82)

Mass spectrum: (M+H)⁺=340/342 (chlorine isotope)

R_(f) value: 0.80 (silica gel; dichloromethane/methanol=19:1)

(c) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine

Prepared analogously to Example 1g from (1S)-N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine and TFA in dichloromethane.

Yield: 31%

C₁₁H₁₄ClN₃O (239.70)

Mass spectrum: (M+H)⁺=240/242 (chlorine isotope)

R_(f) value: 0.10 (silica gel; dichloromethane/ethanol=9:1)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.

Yield: 59%

C₂₃H₂₅ClN₄O₄ (456.92)

Mass spectrum: (M+H)⁺=457/459 (chlorine isotope)

R_(f) value: 0.51 (silica gel; dichloromethane/ethanol=9:1)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 148

Σ: 57% (M + H)⁺ = 427/429 (chlorine isotope) 0.5 (silica gel; dichloromethane/ ethanol = 9:1) N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-methyl-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide 88

Σ: 3.6% (M + H)⁺ = 465/467 (chlorine isotope) 2.38 min N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(furan-2-yl)-methyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide

Example 82 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamide

(a) methyl 3-chloro-4-nitroso-benzoate

8.00 g (29.6 mmol) potassium peroxodisulphate are added to 6.0 ml of conc. sulphuric acid with stirring, stirred for 30 minutes at ambient temperature under a nitrogen atmosphere, the mixture is stirred into 50 g ice and neutralised with 14 g sodium carbonate. The solution obtained is combined with a suspension of 2.78 g (15.0 mmol) methyl 4-amino-3-chloro-benzoate in 300 ml of water and stirred for 16 hours at ambient temperature. The reaction mixture is suction filtered, the filter cake is washed with water, dried in the air and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1).

Yield: 1.00 g (33%)

C₈H₆ClNO₃ (199.59)

Mass spectrum: (M+H)⁺=199/201 (chlorine isotope)

R_(f) value: 0.55 (silica gel; petroleum ether/ethyl acetate=4:1)

(b) methyl 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoate

1.00 g (5.01 mmol) methyl 3-chloro-4-nitroso-benzoate are placed in 10 ml chloroform and a freshly prepared solution of 1.10 g (20.3 mmol) butadiene in 6 ml chloroform is added dropwise with stirring at 0° C. The reaction mixture is stirred for 30 minutes at 0-10° C. and for 16 hours at ambient temperature, evaporated down i. vac. and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=19:1).

Yield: 1.00 g (79%)

C₁₂H₁₂ClNO₃ (253.68)

Mass spectrum: (M+H)⁺=254/256 (chlorine isotope)

R_(f) value: 0.50 (silica gel; petroleum ether/ethyl acetate=4:1)

(c) 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoic acid

Prepared analogously to Example 2d from methyl 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoate and sodium hydroxide in a solvent mixture of water and ethanol.

Yield: 90%

C₁₁H₁₀ClNO₃ (239.66)

Mass spectrum: (M−H)⁻=238/240

R_(f) value: 0.20 (silica gel; petroleum ether/ethyl acetate=4:1)

(d) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamide

Prepared analogously to Example 1f from 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF.

Yield: 88%

C₂₀H₁₈Cl₂N₄O₂ (417.29)

Mass spectrum: (M+H)⁺=417/419/421 (chlorine isotope)

R_(f) value: 0.35 (silica gel; petroleum ether/ethyl acetate=1:1)

Example 83 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzamide

(a) 2-chloro-N-(4-chlorbutyl-sulphonyl)-4-methyl-aniline

1.30 ml (10.7 mmol) 2-chloro-4-methyl-aniline are placed in 30 ml of pyridine, combined with 2.67 g (10.5 mmol) 75% m 4-chlorobutyl-sulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with 6-molar hydrochloric acid, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=9:1->7:3).

Yield: 1.27 g (40%)

C₁₁H₁₅Cl₂NO₂S (296.21)

Mass spectrum: (M+H)⁺=296/298/300 (chlorine isotope)

R_(f) value: 0.42 (silica gel; petroleum ether/ethyl acetate=4:1)

(b) 3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-toluene

1.27 g (4.29 mmol) 2-chloro-N-(4-chlorbutyl-sulphonyl)-4-methyl-aniline are stirred together with 722 mg (6.43 mmol) potassium-tert.-butoxide in 50 ml DMF for 16 hours at 60° C. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=3:2).

Yield: 850 mg (76%)

C₁₁H₁₄ClNO₂S (259.75)

Mass spectrum: (M+H)⁺=260/262 (chlorine isotope)

R_(f) value: 0.27 (silica gel; petroleum ether/ethyl acetate=4:1)

(c) 3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzoic acid

250 mg (0.96 mmol) 3-chloro-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-toluene are suspended in 10 ml of water and combined with 456 mg (2.89 mmol) potassium permanganate and 39 mg (0.98 mmol) sodium hydroxide. The reaction mixture is refluxed for 4 hours. After cooling to ambient temperature sodium thiosulphate is added to decolorise the mixture which is then extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol=19:1).

Yield: 50 mg (18%)

C₁₁H₁₂ClNO₄S (289.74)

Mass spectrum: (M+H)⁺=290/292

R_(t) value: 2.50 min

(d) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazinan-2-yl)-benzamide

Prepared analogously to Example 1f from 3-chloro-4-(1,2-dioxo-[1,2]thiazinan-2-yl)-benzoic acid, (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.

Yield: 34%

C₂₁H₂₂Cl₂ N₄O₄S (497.40)

Mass spectrum: (M+H)⁺=497/499/501 (chlorine isotope)

R_(t) value: 2.53 min

Example 84 N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide

(a) methyl 4-(5-chloropentyl-sulphonyl-amino)-3-methyl-benzoate

Prepared analogously to Example 83a from methyl 4-amino-3-methyl-benzoate and 5-chloropentyl-sulphonic acid chloride in pyridine. Yield: 43%

C₁₄H₂₀ClNO₄S (333.83)

Mass spectrum: (M+H)⁺=334/336 (chlorine isotope)

R_(f) value: 0.72 (silica gel; petroleum ether/ethyl acetate=7:3)

(b) methyl 4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzoate

Prepared analogously to Example 83b from methyl 4-(5-chloropentyl-sulphonyl-amino)-3-methyl-benzoate and potassium-tert.-butoxide in DMF.

Yield: 19%

C₁₄H₁₉NO₄S (297.37)

Mass spectrum: (M+H)⁺=298

R_(t) value: 0.30 (silica gel; petroleum ether/ethyl acetate=4:1)

(c) 4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzoic acid

Prepared analogously to Example 39d from methyl 4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzoate and lithium hydroxide in a solvent mixture of water and ethanol.

Yield: 60%

C₁₃H₁₇NO₄S (283.34)

Mass spectrum: (M+H)⁺=284

R_(t) value: 2.60 min

(d) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide

Prepared analogously to Example 1f from 4-(1,2-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzoic acid, (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and NMM in DMF with subsequent purification by chromatography on silica gel.

Yield: 75%

C₂₃H₂₇ClN₄O₄S (491.00)

Mass spectrum: (M+H)⁺=491/493 (chlorine isotope)

R_(t) value: 2.60 min

Example 89 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-([1,2]oxazinan-2-yl)-benzamide

209 mg (0.50 mmol) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzamide together with 100 mg 10% palladium charcoal in 5 ml of ethyl acetate for 7 minutes are hydrogenated at ambient temperature at 5 bar under a hydrogen atmosphere. Then the mixture is suction filtered, the filtrate is evaporated down i. vac. and evaporated again with ether.

Yield: 200 mg (95%)

C₂₀H₂₀Cl₂N₄O₂ (419.30)

Mass spectrum: (M+H)⁺=419/421/423 (chlorine isotope)

R_(f) value: 0.40 (silica gel; petroleum ether/ethyl acetate=1:1)

Example 90 N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzamide

(a) ethyl 3-(2-benzyloxy-ethoxy)-propionate

8.53 ml (60.0 mmol) benzyloxy-ethanol are combined with 13 mg (0.57 mmol) sodium in 40 ml THF, then when it has dissolved 5.95 ml (54.7 mmol) ethyl acrylate are added under an argon atmosphere and stirred for 20 hours at ambient temperature. After neutralising with 0.6 ml 1-molar hydrochloric acid the reaction mixture is evaporated down i. vac., the residue is taken up in sat. sodium chloride solution and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=4:1).

Yield: 3.73 g (25%)

C₁₄H₂₀O₄ (252.31)

Mass spectrum: (M+H)⁺=253

R_(f) value: 0.48 (silica gel; petroleum ether/ethyl acetate=4:1)

(b) ethyl 3-(2-hydroxy-ethoxy)-propionate

3.73 g (14.8 mmol) ethyl 3-(2-benzyloxy-ethoxy)-propionate are hydrogenated together with 665 mg 10% palladium charcoal in 70 ml of ethanol for 44 minutes at ambient temperature under a hydrogen atmosphere at 3 bar. Then the mixture is suction filtered and the filtrate is evaporated down i. vac.

Yield: 2.26 g (94%)

C₇H₁₄O₄ (162.18)

Mass spectrum: (M+H)⁺=163

(c) ethyl 3-(2-chloro-ethoxy)-propionate

2.26 g (13.9 mmol) ethyl 3-(2-hydroxy-ethoxy)-propionate are suspended in 5 ml (68.5 mmol) thionyl chloride and 20 μl (0.27 mmol) DMF are added. The reaction mixture is refluxed for 4 hours and then evaporated down i. vac. The product is further reacted without any more purification.

Yield: quant.

C₇H₁₃O₃ (180.63)

Mass spectrum: (M+H)⁺=181/183 (chlorine isotope)

(d) 3-(2-chloro-ethoxy)-propionic acid

2.00 g (11.1 mmol) ethyl 3-(2-chloro-ethoxy)-propionate are suspended in 8 ml of ethanol and 4.96 ml (16.6 mmol) of 8% lithium hydroxide solution are added. The mixture is stirred for 4 hours at ambient temperature, then evaporated down i. vac., acidified with 2-molar hydrochloric acid, combined with diethyl ether and dried over sodium sulphate. Then it is filtered off and evaporated down i. vac.

Yield: 1.51 g (89%)

C₅H₉ClO₃ (152.58)

Mass spectrum: (M−H)⁻=151/153 (chlorine isotope)

(e) 3-(2-chloro-ethoxy)-propionic acid-chloride

Prepared analogously to Example 90c from 3-(2-chloro-ethoxy)-propionic acid and thionyl chloride with DMF.

Yield: 91%

C₅H₈Cl₂O₂ (171.02)

(f) methyl 4-[3-(2-chloro-ethoxy)-propionyl-amino]-3-methyl-benzoate

1.70 g (10.3 mmol) methyl 4-amino-3-methyl-benzoate in 10 ml THF are combined with 2.84 ml (20.6 mmol) triethylamine and stirred for 20 minutes at ambient temperature. Then a solution of 1.78 g (10.4 mmol) 3-(2-chloro-ethoxy)-propionic acid-chloride in 25 ml THF is added dropwise and the mixture is stirred for a further 2.5 hours at ambient temperature. Then water is added and the mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=7:3->6:4).

Yield: 1.25 g (41%)

C₁₄H₁₈ClNO₄ (299.75)

Mass spectrum: (M+H)⁺=300/302 (chlorine isotope)

R_(f) value: 0.15 (silica gel; petroleum ether/ethyl acetate=7:3)

(g) methyl 3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoate

900 mg (3.00 mmol) 4-[3-(2-chloro-ethoxy)-propionyl-amino]-3-methyl-benzoate methyl are stirred in 40 ml DMF together with 520 mg (4.63 mmol) potassium tert.-butoxide and 12 mg (80 μmol) sodium iodide for 3 hours at 60° C. After evaporation i. vac. the residue is combined with water, extracted with ethyl acetate and the combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=11:9).

Yield: 310 mg (39%)

C₁₄H₁₇NO₄ (263.29)

Mass spectrum: (M+H)⁺=264

(h) 3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoic acid

Prepared analogously to Example 39d from methyl 3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoate and lithium hydroxide in a solvent mixture of water and ethanol.

Yield: 69%

C₁₃H₁₅NO₄ (249.26)

Mass spectrum: (M+H)⁺=250

R_(t) value: 2.06 min

(i) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(5-oxo-[1,4]oxazepan-4-yl)-benzoic acid, (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.

Yield: 83%

C₂₃H₂₅ClN₄O₄ (456.92)

Mass spectrum: (M+H)⁺=457/459 (chlorine isotope)

R_(t) value: 2.23 min

Example 91 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzamide

(a) methyl 4-(3-[1,1-dimethyl-2-hydroxy-ethyl]ureido)-3-methyl-benzoate

5.70 g (29.8 mmol) methyl 4-isocyanato-3-methyl-benzoate are dissolved in 100 ml THF and a solution of 2.86 ml (30.0 mmol) 2-amino-2-methyl-propan-1-ol in 25 ml THF is added dropwise. The mixture is stirred for 2 hours at ambient temperature and then evaporated down i. vac. The residue is further reacted without any more purification.

Yield: 8.40 g (quant.)

C₁₄H₂₀N₂O₄ (280.32)

Mass spectrum: (M−H)⁻=279

R_(f) value: 0.20 (silica gel; dichloromethane/ethanol=19:1)

(b) methyl 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoate

7.00 g (25.0 mmol) methyl 4-(3-[1,1-dimethyl-2-hydroxy-ethyl]-ureido)-3-methyl-benzoate are dissolved in 400 ml THF at 0° C. and combined with 6.73 g (60.0 mmol) potassium-tert.-butoxide. After stirring for 15 minutes at 0° C. a solution of 5.72 g (30.0 mmol) p-toluenesulphonic acid in 50 ml THF is added dropwise. After another 10 minutes stirring at 0° C. 300 ml of water are added, the mixture is neutralised with 1-molar hydrochloric acid and the THF is removed i. vac. The residue is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. Then the residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol=100:0->97:3).

Yield: 2.50 g (38%)

C₁₄H₁₈N₂O₃ (262.30)

Mass spectrum: (M+H)⁺=263

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=19:1)

(c) 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoic acid

2.70 g (10.3 mmol) methyl 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoate are suspended in 75 ml of methanol and combined with a solution of 1.68 g (30.0 mmol) potassium hydroxide in 10 ml of water. It is stirred for 3 hours at ambient temperature and then evaporated down i. vac. The aqueous residue is diluted with water, acidified with 1-molar hydrochloric acid and the precipitate obtained is suction filtered, washed with water and dried.

Yield: 2.30 g (90%)

C₁₃H₁₆N₂O₃ (248.28)

Mass spectrum: (M+H)⁺=249

R_(f) value: 0.50 (silica gel; dichloromethane/methanol=9:1)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide

Prepared analogously to Example 1f from 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THF and purification of the residue by chromatography on silica gel.

Yield: 59%

C₂₂H₂₄ClN₅O₂ (425.91)

Mass spectrum: (M+H)⁺=426/428 (chlorine isotope)

R_(f) value: 0.40 (silica gel; dichloromethane/methanol=9:1)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value No. Name 92

Σ: 29% (M + H)⁺ = 456/458 (chlorine isotope) 0.45 (silica gel, CH₂Cl₂/ C₂H₅OH 9:1) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4,4- dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzamide

Example 93 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide

(a) 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzonitrile

4.00 g (25.7 mmol) 3-chloro-4-fluoro-benzonitrile are heated to 60° C. in 20 ml DMSO with 8.00 g (106.5 mmol) 2-amino-1-propanol with stirring for 2 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.

Yield: 5.20 g (96%)

C₁₀H₁₁ClN₂O (210.66)

Mass spectrum: (M+H)⁺=211/213 (chlorine isotope)

R_(f) value: 0.27 (silica gel; dichloromethane/methanol=19:1)

(b) 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoic acid

5.20 g (24.7 mmol) 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzonitrile are refluxed for 6 hours in 50 ml of conc. hydrochloric acid with stirring. Then the mixture is evaporated down i. vac., made basic with conc. ammonia solution and extracted with ethyl acetate. After acidification of the aqueous phase with acetic acid the mixture is extracted with ethyl acetate, the combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.

Yield: 5.00 g (88%)

C₁₀H₁₂ClNO₃ (229.66)

Mass spectrum: (M+H)⁺=230/232 (chlorine isotope)

R_(f) value: 0.44 (silica gel; dichloromethane/methanol=9:1)

(c) ethyl 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate

5.00 g (21.8 mmol) 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoic acid are stirred for 16 hours in 100 ml sat. ethanolic hydrochloric acid at ambient temperature and then evaporated down i. vac. The residue is combined with water and conc. ammonia solution and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is purified by chromatography on silica gel (eluant: dichloromethane/methanol=50:1).

Yield: 3.40 g (61%)

C₁₂H₁₆ClNO₃ (257.71)

Mass spectrum: (M+H)⁺=258/260 (chlorine isotope)

R_(f) value: 0.34 (silica gel; dichloromethane/methanol=19:1)

(d) ethyl 3-chloro-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoate

0.50 g (1.94 mmol) ethyl 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate are placed in 30 ml THF together with 0.22 g (2.20 mmol) triethylamine and 1.10 ml (2.08 mmol) 20% phosgene solution in toluene is added with stirring at ambient temperature. The mixture is stirred for 1 hour at ambient temperature, then 1 ml of water is added and the mixture is stirred for another 10 minutes. The mixture is then evaporated down i. vac., combined with water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac.

Yield: 0.54 g (98%)

C₁₃H₁₄ClNO₄ (283.71)

Mass spectrum: (M+H)⁺=284/286 (chlorine isotope)

R_(f) value: 0.71 (silica gel; dichloromethane/methanol=19:1)

(e) 3-chloro-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoic acid

0.90 g (3.17 mmol) ethyl 3-chloro-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoate are stirred for 1 hour in 50 ml of methanol with 10 ml 1-molar aqueous lithium hydroxide solution at ambient temperature. The mixture is then evaporated down to 20 ml i. vac., acidified with conc. hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over sodium sulphate and evaporated down i. vac. The residue is crystallised from a little diethyl ether and suction filtered.

Yield: 0.45 g (56%)

C₁₁H₁₀ClNO₄ (255.65)

Mass spectrum: (M+H)⁺=256/258 (chlorine isotope)

R_(f) value: 0.26 (silica gel; dichloromethane/methanol=9:1)

(f) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(4-methyl-2-oxo-oxazolidin-3-yl)-benzamide

Prepared analogously to Example 1f from 3-chloro-(4-methyl-2-oxo-oxazolidin-3-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and DIPEA in THF and purification of the residue by chromatography on aluminium oxide.

Yield: 45%

C₂₀H₁₈Cl₂N₄O₃ (433.29)

Mass spectrum: (M+H)⁺=433/435/437 (chlorine isotope)

R_(f) value: 0.65 (silica gel; dichloromethane/methanol=9:1)

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 94

Σ: 18% (M + H)⁺ = 463/465/467 (chlorine isotope) 0.60 (silica gel, CH₂Cl₂/ CH₃OH 19:1) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(4- methyl-2-oxo-oxazolidin-3-yl)-benzamide 102

Σ: 18% (M + H)⁺ = 443/445 (chlorine isotope) 0.20 (silica gel, CH₂Cl₂/ CH₃OH 19:1) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- ((4S)-4-methyl-2-oxo-oxazolidin-3-yl)-benzamide 103

Σ: 9.4% (M + H)⁺ = 477/479/481 (chlorine isotope) 0.30 (silica gel, CH₂Cl₂/ CH₃OH 19:1) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- (4,4-dimethyl-2-oxo-oxazolidin-3-yl)-benzamide 104

Σ: 13% (M + H)⁺ = 443/445 (chlorine isotope) 0.80 (silica gel, CH₂Cl₂/ CH₃OH 19:1) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4- ((4R)-4-methyl-2-oxo-oxazolidin-3-yl)-benzamide 105

Σ: 18% (M + H)⁺ = 477/479/481 (chlorine isotope) 0.65 (silica gel, CH₂Cl₂/ CH₃OH 19:1) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4- ((4R)-4-ethyl-2-oxo-oxazolidin-3-yl)-benzamide

Example 95

N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-chloro-phenyl)-N-Boc-phenyl-glycinamide and N′-(2-amino-5-chloro-phenyl)-N-Boc-phenyl-glycinamide

Prepared analogously to Example 47a from N-Boc-phenyl-glycine, 4-chloro-1,2-phenylenediamine and DCC in THF.

Yield: quant. mixture of the two regioisomers

C₁₉H₂₂ClN₃O₃ (375.85)

Mass spectrum: (M+H)⁺=376/378 (chlorine isotope)

R_(f) value: 0.41 (silica gel; dichloromethane/ethanol=19:1)

(b) N-acetyl-1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine

3.65 g (9.71 mmol) of the mixture obtained in 95a are dissolved in 8 ml acetic acid and refluxed for 6 hours with stirring. The reaction mixture is evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol=100:0->94:6).

Yield: 1.34 g (46%)

C₁₆H₁₄ClN₃O (299.76)

Mass spectrum: (M+H)⁺=300/302 (chlorine isotope)

R_(f) value: 0.19 (silica gel; dichloromethane/ethanol=19:1)

(c) 1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine

1.34 g (4.47 mmol) N-acetyl-1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine in 9 ml of ethanol are combined with 18 ml of conc. hydrochloric acid and heated to 50° C. for 2 days. The reaction mixture is evaporated down i. vac. and twice taken up in ethanol and evaporated down again.

Yield: 1.26 g (96%)

C₁₄H₁₂ClN₃.HCl (294.18/257.72)

Mass spectrum: (M+H)⁺=258/260 (chlorine isotope)

(d) N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, 1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine, TBTU and DIPEA in THF.

Yield: 89%

C₂₆H₂₃ClN₄O₃ (474.94)

Mass spectrum: (M+H)⁺=475/477 (chlorine isotope)

R_(f) value: 0.68 (silica gel; dichloromethane/ethanol=9:1)

The following compound is prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 108

Σ: 12% (M + H)⁺ = 437/439 (chlorine isotope) 0.51 (silica gel, CH₂Cl₂/ ethanol = 9:1) N-[1-(1S)-(5-chloro-1H-benzimidazol-2-yl)-2-cyano-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide 140

Σ: 2.9% (M + H)⁺ = 455/457 (chlorine isotope) 0.60 (silica gel, CH₂Cl₂/ C₂H₅OH 9:1) N-[1-(5-chloro-1H-benzimidazol-2-yl)-3-methyl-butyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide

Example 96 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-chloro-phenyl)-(2S)-2-(Boc-amino)-butyric acid amide and N′-(2-amino-5-chloro-phenyl)-(2S)-2-(Boc-amino)-butyric acid amide

Prepared analogously to Example 47a from (2S)-2-(Boc-amino)-butyric acid, 4-chloro-1,2-phenylenediamine and DCC in THF.

Yield: 89% mixture of the two regioisomers

C₁₅H₂₂ClN₃O₃ (327.81)

Mass spectrum: (M+H)⁺=328/330 (chlorine isotope)

R_(f) value: 0.63 (silica gel; dichloromethane/ethanol=19:1)

(b) (1S)-N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine

Prepared analogously to Example 47b from the mixture obtained in 95a and acetic acid and purification of the residue by chromatography on silica gel.

Yield: 94%

C₁₅H₂₀ClN₃O₂ (309.79)

Mass spectrum: (M+H)⁺=310/312 (chlorine isotope)

R_(f) value: 0.63 (silica gel; dichloromethane/ethanol=19:1)

(c) (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-1-phenyl-methylamine

Prepared analogously to Example 75c from (1S)-N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine and trifluoroacetic acid in dichloromethane.

Yield: quant.

C₁₀H₁₂ClN₃.2 CF₃COOH (437.72/209.68)

Mass spectrum: (M+H)⁺=210/212 (chlorine isotope)

(d) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-propylamine, TBTU and DIPEA in THF.

Yield: 17%

C₂₂H₂₃ClN₄O₃ (426.90)

Mass spectrum: (M+H)⁺=427/429 (chlorine isotope)

R_(f) value: 0.45 (silica gel; dichloromethane/ethanol=9:1)

The following compounds were prepared analogously:

structural formula Yield mass peak(s) R_(f) value or R_(t) No. Name 107

Σ: 4.0% (M + H)⁺ = 465/467 (chlorine isotope) 0.15 (silica gel, CH₂Cl₂/ CH₃OH 9:1) N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1H-pyrazol-3-yl)-methyl]-3-methyl- 4-(morpholin-3-on-4-yl)-benzamide 141

Σ: 62% (M − H)⁻ = 519/521 (chlorine isotope) 0.54 (silica gel, CH₂Cl₂/ C₂H₅OH 9:1) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-benzyloxy-ethyl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide 149

Σ: 54% (M − H)⁻ = 453/455 (chlorine isotope) 0.55 (silica gel, CH₂Cl₂/ C₂H₅OH 9:1) N-[3-(5-chloro-1H-benzimidazol-2-yl)-tetrahydrofuran-3-yl]-3-methyl-4- (morpholin-3-on-4-yl)-benzamide

Example 106 N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-(morpholin-3-on-4-yl)-benzamide

(a) ethyl 4-[(2-chloro-ethoxy)-acetyl-amino]-3-fluoro-benzoate

Prepared analogously to Example 46a from (2-chloro-ethoxy)-acetylchloride and ethyl 4-amino-3-fluoro-benzoate with TEA in THF.

Yield: 44%

C₁₃H₁₅ClFNO₄ (303.71)

Mass spectrum: (M+H)⁺=304/306 (chlorine isotope)

R_(f) value: 0.29 (silica gel; dichloromethane)

(b) 4-(2-carboxymethoxy-ethylamino)-3-fluoro-benzoic acid

580 mg (1.91 mmol) ethyl 4-[(2-chloro-ethoxy)-acetyl-amino]-3-fluoro-benzoate in 6 ml dioxane are combined with 3.82 ml (7.64 mmol) 2-molar potassium hydroxide solution and 2 ml of water. Then the mixture is heated to 70° C. for 2 h, then diluted with water and acidified with 6-molar hydrochloric acid. After the addition of dichloromethane the precipitate formed is suction filtered and dried in the drying cupboard at 50° C.

Yield: 390 mg (79%)

C₁₁H₁₂FNO₅ (257.22)

Mass spectrum: (M+H)⁺=258

R_(f) value: 0.66 (reversed phase RP-8; methanol/5% NaCl solution=6:4)

(c) 3-fluoro-4-(morpholin-3-on-4-yl)-benzoic acid-chloride

Prepared analogously to Example 41c from 4-(2-carboxymethoxy-ethylamino)-3-fluoro-benzoic acid and thionylchloride in dichloromethane with DMF.

Yield: quant.

C₁₁H₉CIFNO₃ (257.65)

(d) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-fluoro-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 41d from 3-fluoro-4-(morpholin-3-on-4-yl)-benzoic acid-chloride and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine with TEA in THF.

Yield: 47%

C₂₁H₂₀ClFN₄O₄ (446.86)

Mass spectrum: (M+H)⁺=447/449 (chlorine isotope)

R_(f) value: 0.40 (silica gel; dichloromethane/ethanol=9:1)

Example 109 N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) N′-(2-amino-4-chloro-phenyl)-2-(Boc-amino)-2-(pyridin-3-yl)-acetic acid amide and N′-(2-amino-5-chloro-phenyl)-2-(Boc-amino)-2-(pyridin-3-yl)-acetic acid amide

1.00 g (3.96 mmol) N-Boc-amino-2-(pyridin-3-yl)-acetic acid are placed together with 0.59 g (4.16 mmol) 4-chloro-1,2-phenylenediamine at 0° C. in 20 ml THF and 2.92 ml (4.96 mmol) 50% PPA solution in ethyl acetate and 1.24 ml (8.92 mmol) TEA are added. After stirring for 30 min at 0° C. the mixture is stirred for 5 h at ambient temperature stirred and then evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol=10:0->9:1).

Yield: 1.32 g (88%) mixture of the two regioisomers

C₁₈H₂₁ClN₄O₃ (376.84)

Mass spectrum: (M+H)⁺=377/379 (chlorine isotope)

R_(f) value: 0.40 (silica gel; dichloromethane/ethanol=9:1)

(b) N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine

Prepared analogously to Example 47b from the product obtained in Example 111a and acetic acid.

Yield: 81%

C₁₈H₁₉ClN₄O₂ (358.82)

Mass spectrum: (M+H)⁺=359/361 (chlorine isotope)

R_(f) value: 0.51 (silica gel; dichloromethane/ethanol=9:1)

(c) 1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine

Prepared analogously to Example 1g from N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine and trifluoroacetic acid in dichloromethane.

Yield: 66%

C₁₃H₁₁ClN₄ (258.71)

Mass spectrum: (M+H)⁺=259/261 (chlorine isotope)

R_(f) value: 0.62 (silica gel; dichloromethane/ethanol=9:1)

(d) N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and 1-(5-chloro-1H-benzimidazol-2-yl)-1-(pyridin-3-yl)-methylamine with TBTU and DIPEA in THF.

Yield: 84%

C₂₅H₂₂ClN₅O₃ (475.93)

Mass spectrum: (M+H)⁺=476/478 (chlorine isotope)

R_(f) value: 0.31 (silica gel; dichloromethane/ethanol=9:1)

Example 110

N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) methyl ethoxycarbonyl-methoxyimino-(1-methyl-pyrazol-3-yl]-acetate

5.00 g (20.7 mmol) ethoxycarbonyl-methoxyimino-(pyrazol-3-yl)-acetic acid are placed in 20 ml DMF together with 5.73 g (41.5 mmol) potassium carbonate at ambient temperature, stirred until the development of gas has ended, then 2.58 ml (41.5 mmol) of methyl iodide are added and the mixture is stirred for 2 h at 50° C. After evaporation of the reaction mixture i. vac. the residue is combined with water and ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=80:20->65:35).

Yield: 2.61 g (26%) in admixture with regioisomers

C₁₁H₁₅N₃O₅ (269.25)

Mass spectrum: (M+H)⁺=270

R_(f) value: 0.25 (silica gel; petroleum ether/ethyl acetate=1:1)

(b) methyl 2-amino-2-(1-methyl-pyrazol-3-yl)-acetate

2.61 g (9.69 mmol) methyl ethoxycarbonyl-methoxyimino-(1-methyl-pyrazol-3-yl)-acetate are hydrogenated in 60 ml of ethanol with 1.1 g 5% palladium charcoal for 16 h at 50° C. under 3.4 bars pressure in a hydrogen atmosphere. Then the mixture is suction filtered and the filtrate is evaporated down completely i. vac.

Yield: 1.90 g (quant.), slightly contaminated

C₇H₁₁N₃O₂ (169.18)

Mass spectrum: (M+H)⁺=170

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=9:1)

(c) methyl N-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetate

Prepared analogously to Example 1d from methyl 2-amino-2-(1-methyl-pyrazol-3-yl)-acetate and di-tert. butyl pyrocarbonate with TEA in dichloromethane.

Yield: 81%

C₁₂H₁₉N₃O₄ (269.30)

Mass spectrum: (M+H)⁺=270

(d) N-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetic acid

1.16 g (4.31 mmol) methyl N-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetate in 16 ml THF are combined with 10 ml of water and 10 ml of 1-molar lithium hydroxide solution are added. After stirring at ambient temperature for 2 h the mixture is evaporated down i. vac., the residue is combined with water, filtered and the filtrate is adjusted to pH 5 with potassium hydrogen sulphate solution. After total evaporation i. vac. the residue is treated with dichloromethane and a little ethanol, suction filtered and the filtrate is evaporated down completely i. vac.

Yield: 0.92 g (84%)

C₁₁H₁₇N₃O₄ (255.27)

Mass spectrum: (M+H)⁺=256

R_(f) value: 0.15 (silica gel; dichloromethane/ethanol=8:2)

(e) N′-(2-amino-4-chloro-phenyl)-2-(Boc-amino)-2-(1-methyl-pyrazol-3-yl)-acetic acid amide and N′-(2-amino-5-chloro-phenyl)-2-(Boc-amino)-2-(1-methyl-pyrazol-3-yl)-acetic acid amide

Prepared analogously to Example 111a from N-Boc-2-amino-2-(1-methyl-pyrazol-3-yl)-acetic acid and 4-chloro-1,2-phenylenediamine with PPA in ethyl acetate and NMM in dichloromethane.

Yield: 55% mixture of the two regioisomers

C₁₇H₂₂ClN₅O₃ (379.84)

R_(f) value: 0.61 (silica gel; dichloromethane/ethanol=9:1)

(f) N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine

Prepared analogously to Example 47b from the product obtained in Example 112e and acetic acid.

Yield: 81%

C₁₇H₂₀ClN₅O₂ (361.83)

Mass spectrum: (M+H)⁺=362/364 (chlorine isotope)

R_(f) value: 0.60 (silica gel; dichloromethane/ethanol=9:1)

(g) 1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine

Prepared analogously to Example 1g from N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine and trifluoroacetic acid in dichloromethane.

Yield: 77%

C₁₂H₁₂ClN₅ (261.71)

Mass spectrum: (M−NH₃+H)⁺=245/247 (chlorine isotope)

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol/conc. ammonia solution=9:1:0.1)

(h) N-[1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and 1-(5-chloro-1H-benzimidazol-2-yl)-1-(1-methyl-pyrazol-3-yl)-methylamine with TBTU and DIPEA in THF.

Yield: 38%

C₂₄H₂₃ClN₆O₃ (478.93)

Mass spectrum: (M+H)⁺=479/481 (chlorine isotope)

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=9:1)

Example 111 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(5-methyl-morpholin-3-on-4-yl)-benzamide

(a) ethyl 412-(tert.-butoxycarbonyl-methoxy)-1-methyl-ethylamino]-3-chloro-benzoate

1.12 g (4.35 mmol) ethyl 3-chloro-4-(2-hydroxy-1-methyl-ethylamino)-benzoate are combined in 10 ml DMF with 0.21 g (4.78 mmol) 55% sodium hydride dispersion and stirred for 5 min at ambient temperature. Then 0.67 ml tert.-butyl bromoacetate are added and the mixture is stirred for a further 16 h at ambient temperature. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over sodium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=95:5->80:20)

Yield: 230 mg (14%)

C₁₈H₂₆ClNO₅ (371.86)

Mass spectrum: (M+H)⁺=372/374 (chlorine isotope)

R_(f) value: 0.65 (silica gel; petroleum ether/ethyl acetate=7:3)

(b) ethyl 3-chloro-4-[2-(hydroxycarbonyl-methoxy)-1-methyl-ethylamino]-benzoate

Prepared analogously to Example 1g from ethyl 442-(tert.-butoxycarbonyl-methoxy)-1-methyl-ethylamino]-3-chloro-benzoate and trifluoroacetic acid in dichloromethane.

Yield: 87%

C₁₄H₁₈ClNO₅ (315.75)

Mass spectrum: (M+H)⁺=316/318

R_(f) value: 0.40 (silica gel; dichloromethane/ethanol=9:1)

(c) ethyl 3-chloro-4-(5-methyl-momholin-3-on-4-yl)-benzoate

Prepared analogously to Example 41c from ethyl 3-chloro-4-[2-(hydroxycarbonyl-methoxy)-1-methyl-ethylamino]-benzoate and thionyl chloride with DMF in dichloromethane.

Yield: 69% (contaminated)

C₁₄H₁₆ClNO₄ (297.73)

Mass spectrum: (M+H)⁺=298/300 (chlorine isotope)

R_(f) value: 0.40 (silica gel; dichloromethane/ethanol=19:1)

(d) 3-chloro-4-(5-methyl-morpholin-3-on-4-yl)-benzoic acid

Prepared analogously to Example 31b from ethyl 3-chloro-4-(5-methyl-morpholin-3-on-4-yl)-benzoate with lithium hydroxide in THF and water.

Yield: 91%

C₁₂H₁₂ClNO₄ (269.68)

R_(f) value: 0.30 (silica gel; dichloromethane/ethanol=9:1)

(e) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(5-methyl-morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-chloro-4-(5-methyl-morpholin-3-on-4-yl)-benzoic acid and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine with TBTU and TEA in DMF.

Yield: 28%

C₂₂H₂₂Cl₂N₄O₄ (477.34)

Mass spectrum: (M−H)⁻=475/477/479 (chlorine isotope)

R_(f) value: 0.50 (silica gel; dichloromethane/ethanol=9:1)

Example 112 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3-dimethylamino-pyrrolidin-1-yl)-benzamide

(a) 3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzonitrile

0.75 g (4.82 mmol) 3-chloro-4-fluoro-benzonitrile together with 0.65 ml (0.58 g, 5.06 mmol) 3-dimethylamino-pyrrolidine in 12 ml DMF are combined with 231 mg (5.30 mmol) 55% sodium hydride dispersion at ambient temperature with stirring and under an argon atmosphere. After stirring at ambient temperature for 3.5 h the reaction mixture is poured into water and extracted with ethyl acetate after thorough mixing. The combined organic phases are washed with sat. sodium chloride solution, dried over magnesium sulphate and evaporated down completely i. vac.

Yield: 1.11 g (92%)

C₁₃H₁₆ClN₃ (249.74)

Mass spectrum: (M+H)⁺=250/252 (chlorine isotope)

R_(f) value: 0.42 (silica gel; petroleum ether/ethyl acetate=1:1)

(b) 3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzoic acid

Prepared analogously to Example 13b from 3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzonitrile with 10-molar sodium hydroxide solution and ethanol.

Yield: 27%

C₁₃H₁₇ClN₂O₂ (268.74)

Mass spectrum: (M+H)⁺=269/271 (chlorine isotope)

(c) 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(3-dimethylamino-pyrrolidin-1-yl)-benzamide

Prepared analogously to Example 1f from 3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzoic acid and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine with TBTU and TEA in DMF.

Yield: 74%, slightly contaminated

C₂₂H₂₅Cl₂N₅O (446.37)

Mass spectrum: (M+H)⁺=446/448/450 (chlorine isotope)

R_(f) value: 0.65 (silica gel; dichloromethane/methanol=8:2+0.5% conc. ammonia solution)

Example 113 N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzamide

(a) 4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzonitrile

1.00 g (5.29 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile are stirred together with 1.35 g (12.0 mmol) potassium-tert.-butoxide in 4 ml DMSO at ambient temperature under an argon atmosphere for 35 min and then 1.00 g (8.16 mmol) pyrazolidin-3-on-hydrochloride in 3 ml DMSO are added. After stirring at ambient temperature for 68 h the reaction mixture is poured into semisat. sodium chloride solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down completely i. vac.

Yield: 0.58 g (43%)

C₁₁H₈F₃N₃O (255.20)

Mass spectrum: (M+H)⁺=256

R_(f) value: 0.15 (silica gel; dichloromethane+0.5% conc. ammonia solution)

(b) 4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzoic acid

Prepared analogously to Example 13b from 3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzonitrile with 10-molar sodium hydroxide solution and ethanol.

Yield: 56%

C₁₁H₉F₃N₂O₃ (274.20)

R_(f) value: 0.60 (silica gel; dichloromethane/ethanol=8:2+0.5% acetic acid)

(c) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzamide

Prepared analogously to Example 1f from the 4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzoic acid and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine with TBTU and TEA in DMF.

Yield: 12%, contaminated

C₂₀H₁₇ClF₃N₅O₂.2 CF₃COOH (679.88/451.83)

Mass spectrum: (M+H)⁺=452/454 (chlorine isotope)

R_(f) value: 0.58 (silica gel; dichloromethane/methanol=8:2+0.5% conc. ammonia solution)

Example 127 N-[(1S)-1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-(morpholin-3-on-4-yl)-benzamide

(a) (1S)-N-Boc-147-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butylamine

1.68 g (6.37 mmol) tert.-butyl [1-(2-chloro-acetyl)-3-methyl-butyl]-carbamate in 15 ml of methanol are combined with 819 mg (6.37 mmol) 2-amino-4-chloro-pyridine at ambient temperature with stirring and the mixture is refluxed for 3 days. After evaporation i. vac. the residue is combined with 5% sodium hydrogen carbonate solution and stirred for 20 h at ambient temperature. Then it is extracted with dichloromethane, the combined organic phases are dried over sodium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol=100:0->94:6).

Yield: 180 mg (8%)

C₁₇H₂₄ClN₃O₂ (337.85)

Mass spectrum: (M+H)⁺=338/340 (chlorine isotope)

R_(f) value: 0.61 (silica gel; dichloromethane/ethanol=9:1)

(b) (1S)-147-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butylamine

Prepared analogously to Example 1g from (1S)-N-Boc-1-(7-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butylamine with trifluoroacetic acid in dichloromethane.

Yield: quant.

C₁₂H₁₆ClN₃.2 CF₃CO₂H (465.78/237.73)

Mass spectrum: (M+H)⁺=238/240 (chlorine isotope)

(c) N-[(1S)-1-(5-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butyl]-3-methyl-4-morpholin-3-on-4-yl)-benzamide

Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid and (1S)-1-(5-chloro-imidazo[1,2a]pyridin-2-yl)-3-methyl-butylamine with TBTU and DIPEA in THF.

Yield: quant.

C₂₄H₂₇ClN₄O₃ (454.95)

Mass spectrum: (M+H)⁺=455/457 (chlorine isotope)

R_(f) value: 0.54 (silica gel; dichloromethane/ethanol=9:1)

The Examples that follow describe the preparation of some pharmaceutical formulations which contain as active substance any desired compound of general formula I:

Example I

Dry ampoule containing 75 mg of active substance per 10 ml

Composition:

Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0 ml Preparation:

Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use for injections, the product is dissolved in water.

Example II

Dry ampoule containing 35 mg of active substance per 2 ml

Composition:

Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0 ml Preparation:

Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried.

To produce the solution ready for use for injections, the product is dissolved in water.

Example III

Tablet containing 50 mg of active substance

Composition:

(1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 9 mm.

Example IV

Tablet containing 350 mg of active substance

Composition:

(1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 12 mm.

Example V

Capsules containing 50 mg of active substance

Composition:

(1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg Preparation:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.

Example VI

Capsules containing 350 mg of active substance

Composition:

(1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg Preparation:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.

Example VII

Suppositories containing 100 mg of active substance

1 suppository contains:

Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mg 2,000.0 mg Preparation:

The polyethyleneglycol is melted together with polyethylenesorbitan monostearate. At 40° C. the ground active substance is homogeneously dispersed in the melt. It is cooled to 38° C. and poured into slightly chilled suppository moulds. 

What is claimed is:
 1. A compound of the formula

wherein A denotes a group of the formula

wherein m denotes the number 1 or 2, R^(6a) independently of one another denotes a hydrogen, fluorine, chlorine or bromine atom or a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group and R^(6b) independently of one another may be a hydrogen atom, a C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkyloxycarbonyl or C₁₋₃-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of the formula

wherein m denotes the number 1 or 2, X¹ denotes an oxygen atom or a methylene, —NR^(6b)—, carbonyl or sulphonyl group, X² denotes an oxygen atom or a —NR^(6b) group, X³ denotes a methylene, carbonyl or sulphonyl group, X⁴ denotes an oxygen or sulphur atom, a —NR^(6b) or carbonyl group, X⁵ denotes a carbonyl or sulphonyl group, X⁶ denotes an oxygen atom, a —NR^(6b) or methylene group, X⁷ denotes an oxygen or sulphur atom or a —NR^(6b) group, X⁸ denotes a methylene or carbonyl group, X⁹ denotes a —NR^(6b) or carbonyl group, X¹⁰ denotes a sulphinyl or sulphonyl group and R^(6a) independently of one another denote a hydrogen, fluorine, chlorine or bromine atom or a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group and R^(6b) independently of one another may be a hydrogen atom, a C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or C₁₋₃-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R¹ denotes a hydrogen, fluorine, chlorine or bromine atom, a C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C₂₋₃-alkenyl, C₂₋₃-alkynyl, nitro, amino, C₁₋₃-alkoxy, a mono-, di- or trifluoromethoxy group, R² denotes a hydrogen, fluorine, chlorine or bromine atom or a C₁₋₃-alkyl group, R³ denotes a hydrogen atom, a C₂₋₃-alkenyl or C₂₋₃-alkynyl group or a straight-chain or branched C₁₋₆-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, a C₁₋₅-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, C₁₋₅-alkylcarbonyloxy, C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy, C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy, C₁₋₈-alkyloxycarbonylamino, mercapto, C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphanyl, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphinyl, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphonyl, carboxy, C₁₋₃-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, benzyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₆-cycloalkyleneiminocarbonyl, aminosulphonyl, C₁₋₃-alkylaminosulphonyl, di-(C₁₋₃-alkyl)-aminosulphonyl, C₃₋₆-cycloalkyleneiminosulphonyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₁₋₅-alkylcarbonylamino, C₁₋₃-alkylsulphonylamino, N-(C₁₋₃-alkylsulphonyl)-C₁₋₃-alkylamino, C₃₋₆-cycloalkylcarbonylamino, aminocarbonylamino, C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)-aminocarbonylamino, a 4- to 7-membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino, phenylcarbonylamino or guanidino group, a carboxy, aminocarbonyl, C₁₋₄-alkylaminocarbonyl, C₃₋₆-cycloalkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, C₁₋₄-alkoxycarbonyl, C₄₋₆-cycloalkyleneiminocarbonyl group, a phenyl or heteroaryl, phenylcarbonyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, C₁₋₃-alkyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, hydroxy, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, benzyloxy, carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy, C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy, a 4-to 7-membered cycloalkyleneiminocarbonyl-C₁₋₃-alkoxy, carboxy, C₁₋₃-alkyloxycarbonyl or C₁₋₃-alkyloxy-carbonylamino group, a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-C₁₋₃-alkyl or cycloalkyleneimino-C₁₋₃-alkyl group wherein in the cyclic moiety a methylene group may be replaced by an —NH— group optionally substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group or by an oxygen atom and wherein additionally a methylene group adjacent to the —NH—, —N(C₁₋₃-alkylcarbonyl)- or —N(C₁₋₃-alkyl)- group may be replaced in each case by a carbonyl or sulphonyl group, with the proviso that a cycloalkyleneimino group as hereinbefore defined wherein two nitrogen atoms are separated from one another by precisely one —CH₂— group is excluded, R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group or R³ and R⁴ together with the carbon atom to which they are bound, denote a C₃₋₇-cycloalkyl group, while one of the methylene groups of the C₃₋₇-cycloalkyl group may be replaced by an imino, C₁₋₃-alkylimino, acylimino or sulphonylimino group, R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group, B denotes a group of formula

wherein n denotes the number 1 or 2, R⁷ denotes a hydrogen atom or a C₁₋₃-alkyl, hydroxy, C₁₋₅-alkyloxycarbonyl, carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyl, amino or C₁₋₃-alkylamino group and R⁸ independently of one another denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C₂₋₃-alkenyl or C₂₋₃-alkynyl, a hydroxy, C₁₋₃-alkoxy, trifluoromethoxy, amino, nitro or nitrile group, while, unless otherwise stated, by the term “heteroaryl group” mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C₁₋₃-alkyl, phenyl or phenyl-C₁₋₃-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C₁₋₃-alkyl, phenyl, amino-C₂₋₃-alkyl, C₁₋₃-alkylamino-C₂₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl, a 4- to 7-membered cycloalkyleneimino-C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group and two or three nitrogen atoms, and moreover a phenyl ring optionally substituted by a fluorine, chlorine or bromine atom, a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy group, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or C₃₋₆-cycloalkyleneimino group may be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms and the bond is effected via a nitrogen atom or a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 2. A compound of the formula I according to claim 1, wherein A denotes a group of the formula

wherein m denotes the number 1 or 2, R^(6a) independently of one another denote a hydrogen or fluorine atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group and R^(6b) independently of one another may be a hydrogen atom, a C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or C₁₋₃-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of the formula

wherein m denotes the number 1 or 2, X¹ denotes a methylene, —NR^(6b)—, carbonyl or sulphonyl group, X² denotes an oxygen atom or a —NR^(6b) group, X³ denotes a methylene, carbonyl or sulphonyl group, X⁴ denotes an oxygen or sulphur atom, a —NR^(6b) or carbonyl group, X⁵ denotes a carbonyl or sulphonyl group, X⁸ denotes a carbonyl group, X⁹ denotes a carbonyl group, R^(6a) independently of one another denote a hydrogen or fluorine atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group and R^(6b) independently of one another may be a hydrogen atom, a C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or C₁₋₃-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R¹ denotes a hydrogen, fluorine, chlorine or bromine atom, a C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C₂₋₃-alkenyl, C₂₋₃-alkynyl, nitro, amino, C₁₋₃-alkoxy, a mono-, di- or trifluoromethoxy group, R² denotes a hydrogen, fluorine, chlorine or bromine atom or a C₁₋₃-alkyl group, R³ denotes a C₂₋₃-alkenyl or C₂₋₃-alkynyl group or a straight-chain or branched C₁₋₆-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, a C₁₋₅-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, propargyloxy, benzyloxy, C₁₋₅-alkylcarbonyloxy, C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy, C₁₋₅-alkyloxy-carbonyl-C₁₋₃-alkyloxy, C₁₋₈-alkyloxycarbonylamino, mercapto, C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphanyl, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphinyl, C₁₋₃-alkylcarbonylamino-C₁₋₃-alkylsulphonyl, carboxy, C₁₋₃-alkyloxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, benzyloxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₆-cycloalkyleneiminocarbonyl, aminosulphonyl, C₁₋₃-alkylaminosulphonyl, di-(C₁₋₃-alkyl)-aminosulphonyl, C₃₋₆-cycloalkyleneiminosulphonyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₁₋₅-alkylcarbonylamino, C₁₋₃-alkylsulphonylamino, N-(C₁₋₃-alkylsulphonyl)-C₁₋₃-alkylamino, C₃₋₆-cycloalkylcarbonylamino, aminocarbonylamino, C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)-aminocarbonylamino, a 4- to 7-membered cycloalkyleneiminocarbonylamino, benzyloxycarbonylamino, phenylcarbonylamino or guanidino group, a carboxy, aminocarbonyl, C₁₋₄-alkylaminocarbonyl, C₃₋₆-cycloalkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, C₁₋₄-alkoxycarbonyl, C₄₋₆-cycloalkyleneiminocarbonyl group, a phenyl or heteroaryl, phenylcarbonyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, C₁₋₃-alkyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, hydroxy, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, benzyloxy, carboxy-C₁₋₃-alkyloxy, C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyloxy, aminocarbonyl-C₁₋₃-alkyloxy, C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyloxy, a 4- to 7-membered cycloalkyleneiminocarbonyl-C₁₋₃-alkoxy, carboxy, C₁₋₃-alkyloxycarbonyl or C₁₋₃-alkyloxy-carbonylamino group, a 3- to 7-membered cycloalkyl, cycloalkyleneimino, cycloalkyl-C₁₋₃-alkyl or cycloalkyleneimino-C₁₋₃-alkyl group wherein in the cyclic moiety a methylene group may be replaced by a —NH— group optionally substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group or by an oxygen atom and wherein additionally a methylene group adjacent to the —NH—, —N(C₁₋₃-alkylcarbonyl)- or —N(C₁₋₃-alkyl)- group may be replaced in each case by a carbonyl or sulphonyl group, with the proviso that a cycloalkyleneimino group as hereinbefore defined wherein two nitrogen atoms are separated from one another by precisely one —CH₂— group is excluded, R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group, R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group, B denotes a group of the formula

wherein n denotes the number 1 or 2, R⁷ denotes a hydrogen atom, a C₁₋₃-alkyl, hydroxy, C₁₋₅-alkyloxycarbonyl, carboxy-C₁₋₃-alkyl, C₁₋₃-alkyloxycarbonyl-C₁₋₃-alkyl, amino or C₁₋₃-alkylamino group and R⁸ independently of one another denote a hydrogen, fluorine, chlorine, bromine or iodine atom, a C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C₂₋₃-alkenyl or C₂₋₃-alkynyl, a hydroxy, C₁₋₃-alkoxy, trifluoromethoxy, amino, nitro or nitrile group, while, unless otherwise stated, by the term “heteroaryl group” mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C₁₋₃-alkyl, phenyl or phenyl-C₁₋₃-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C₁₋₃-alkyl, phenyl, amino-C₂₋₃-alkyl, C₁₋₃-alkylamino-C₂₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl, a 4- to 7-membered cycloalkyleneimino-C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C₁₋₃-alkyl or phenyl-C₁₋₃-alkyl group and two or three nitrogen atoms, and moreover a phenyl ring optionally substituted by a fluorine, chlorine or bromine atom, a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy group, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or C₃₋₆-cycloalkyleneimino group may be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms and the bond is effected via a nitrogen atom or a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 3. A compound of the formula I according to claim 1, wherein A denotes a group of the formula

wherein m denotes the number 1 or 2, R^(6a) independently of one another denote a hydrogen or fluorine atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group and R^(6b) independently of one another may be a hydrogen atom, a C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or C₁₋₃-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 7-membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of the formula

wherein m denotes the number 1 or 2, X¹ denotes a methylene, —NR^(6b)—, carbonyl or sulphonyl group, X² denotes an oxygen atom or a —NR^(6b) group, X³ denotes a methylene, carbonyl or sulphonyl group, X⁴ denotes an oxygen or sulphur atom or a —NR^(6b) group, X⁵ denotes a carbonyl or sulphonyl group, R^(6a) independently of one another denote a hydrogen or fluorine atom, a C₁₋₃-alkyl, hydroxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl or C₁₋₃-alkylcarbonylamino group and R^(6b) independently of one another may be a hydrogen atom, a C₁₋₄-alkyl, C₁₋₄-alkylcarbonyl, C₁₋₄-alkoxycarbonyl or C₁₋₃-alkylsulphonyl group, with the proviso that in the above-mentioned substituted 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R¹ denotes a fluorine, chlorine or bromine atom, a C₁₋₃-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a nitro, C₁₋₃-alkoxy, a mono-, di- or trifluoromethoxy group, R² denotes a hydrogen atom, R³ denotes a straight-chain or branched C₁₋₆-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, benzyloxy, a C₁₋₅-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, C₁₋₅-alkylcarbonyloxy, C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy, C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy, C₁₋₈-alkyloxycarbonylamino, C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy, C₁₋₃-alkyloxycarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₆-cycloalkyleneiminocarbonyl, aminocarbonylamino, C₁₋₃-alkylaminocarbonylamino or di-(C₁₋₃-alkyl)-aminocarbonylamino group, an aminocarbonyl, C₁₋₄-alkylaminocarbonyl, C₃₋₆-cycloalkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group, a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, C₁₋₃-alkyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, hydroxy, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, or C₁₋₃-alkyloxycarbonyl group, a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a methylene group may be replaced by a —NH— group optionally substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group, or an oxygen atom, R⁴ denotes a hydrogen atom, R⁵ denotes a hydrogen atom, B denotes a group of the formula

wherein n denotes the number 1, R⁷ denotes a hydrogen atom and R⁸ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a methyl, C₂₋₃-alkynyl, or methoxy group, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, while, unless otherwise stated, by the term “heteroaryl group” mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C₁₋₃-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C₁₋₃-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C₁₋₃-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 4. A compound of the formula I according to claim 3, wherein A, R¹, R², R⁴, R⁵ and B are defined as in claim 3 and R³ denotes a straight-chain or branched C₁₋₆-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a nitrile, hydroxy, benzyloxy, a C₁₋₅-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, an allyloxy, C₁₋₅-alkylcarbonyloxy, C₁₋₅-alkyloxycarbonyloxy, carboxy-C₁₋₃-alkyloxy, C₁₋₅-alkyloxycarbonyl-C₁₋₃-alkyloxy, C₁₋₈-alkyloxycarbonylamino, C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy, C₁₋₃-alkyloxycarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, C₃₋₆-cycloalkyleneiminocarbonyl, aminocarbonylamino, C₁₋₃-alkylaminocarbonylamino or di-(C₁₋₃-alkyl)-aminocarbonylamino group, an aminocarbonyl, C₁₋₄-alkylaminocarbonyl, C₃₋₆-cycloalkylaminocarbonyl or di-(C₁₋₃-alkyl)-aminocarbonyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 5. A compound of the formula I according to claim 3, wherein A, R¹, R², R⁴, R⁵ are defined as in claim 3 and R³ denotes a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, C₁₋₃-alkyl, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, hydroxy, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, or C₁₋₃-alkyloxycarbonyl group, a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a methylene group may be replaced by a —NH— group optionally substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group, or by an oxygen atom, while, unless otherwise stated, by the term “heteroaryl group” mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C₁₋₃-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C₁₋₃-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C₁₋₃-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 6. A compound of the formula I according to claim 1, wherein A denotes a group of the formula

wherein m denotes the number 1 or 2, R^(6a) independently of one another denote a hydrogen or fluorine atom or a C₁₋₃-alkyl group and R^(6b) may be a hydrogen atom or a C₁₋₃-alkyl group, with the proviso that in the above-mentioned substituted 7 membered groups A the heteroatoms optionally introduced as substituents are not separated from another heteroatom by precisely one carbon atom, or a group of the formula

wherein m denotes the number 1 or 2, X¹ denotes a methylene, —NR^(6b)—, carbonyl or sulphonyl group, X² denotes an oxygen atom or a —NR^(6b) group, X³ denotes a methylene, carbonyl or sulphonyl group, X⁴ an oxygen or sulphur atom or a —NR^(6b) group, X⁵ denotes a carbonyl or sulphonyl group, R^(6a) independently of one another denote a hydrogen or fluorine atom or a C₁₋₃-alkyl group and R^(6b) independently of one another may be a hydrogen atom or a C₁₋₃-alkyl group, with the proviso that in the above-mentioned substituted 7-membered cyclic groups A the heteroatoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R¹ denotes a chlorine or bromine atom, a methyl or methoxy group, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a nitro group, R² denotes a hydrogen atom, R³ denotes a straight-chain or branched C₁₋₄-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C₁₋₄-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy or C₁₋₃-alkyloxycarbonyl group, a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, C₁₋₃-alkyl, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, or C₁₋₃-alkyloxycarbonyl group, R⁴ denotes a hydrogen atom, R⁵ denotes a hydrogen atom and B denotes a group of formula

wherein n denotes the number 1, R⁷ denotes a hydrogen atom and R⁸ denotes a chlorine or bromine atom or the ethynyl group, while, unless otherwise stated, by the term “heteroaryl group” mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C₁₋₃-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C₁₋₃-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C₁₋₃-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 7. A compound of the formula I according to claim 6, wherein A, R¹, R², R⁴, R⁵ and B are defined as in claim 6 and R³ denotes a straight-chain or branched C₁₋₄-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C₁₋₄-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy or C₁₋₃-alkyloxycarbonyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 8. A compound of the formula I according to claim 6, wherein A, R¹, R², R⁴, R⁵ and B are defined as in claim 6 and R³ denotes a phenyl or heteroaryl, phenyl-C₁₋₃-alkyl or heteroaryl-C₁₋₃-alkyl group which is optionally mono- or polysubstituted in the phenyl or heteroaryl moiety by fluorine, chlorine or bromine atoms, C₁₋₃-alkyl, C₁₋₄-alkyloxy, mono-, di- or trifluoromethoxy, carboxy, or C₁₋₃-alkyloxycarbonyl group, a 3- to 7-membered cycloalkyl group wherein in the cyclic moiety a methylene group may be replaced by a —NH— group optionally substituted by a C₁₋₃-alkyl or C₁₋₃-alkylcarbonyl group, or by an oxygen atom, while, unless otherwise stated, by the term “heteroaryl group” mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C₁₋₃-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C₁₋₃-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C₁₋₃-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 9. A compound of the formula I according to claim 1, wherein A denotes a group of the formula

wherein m denotes the number 1 or 2, R^(6a) independently of one another denote a hydrogen or fluorine atom or a C₁₋₃-alkyl group, with the proviso that in the above-mentioned substituted 7-membered cyclic groups A the fluorine atoms introduced as substituents are not separated from another heteroatom by precisely one carbon atom, R¹ denotes a chlorine or bromine atom, a methyl or methoxy group, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or a nitro group, R² denotes a hydrogen atom, R³ denotes a straight-chain or branched C₁₋₄-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C₁₋₄-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy or C₁₋₃-alkyloxycarbonyl group, a furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C₁₋₂-alkyl or imidazolyl-C₁₋₂-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C₁₋₃-alkyl groups, C₁₋₃-alkyloxy groups, carboxy or C₁₋₃-alkyloxycarbonyl groups, and R⁴ denotes a hydrogen atom, R⁵ denotes a hydrogen atom and B denotes a group of the formula

wherein n denotes the number 1, R⁷ denotes a hydrogen atom and R⁸ denotes a chlorine or bromine atom or an ethynyl group, while, unless otherwise stated, by the term “heteroaryl group” mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C₁₋₃-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C₁₋₃-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C₁₋₃-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 10. A compound of the formula I according to claim 9, wherein A, R¹, R², R⁴, R⁵ and B are defined as in claim 9 and R³ denotes a straight-chain or branched C₁₋₄-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, and which is optionally substituted by a hydroxy, a C₁₋₄-alkyloxy group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C₁₋₃-alkylsulphanyl, C₁₋₃-alkylsulphonyl, carboxy or C₁₋₃-alkyloxycarbonyl group, while the alkyl and alkoxy groups contained in the above-mentioned definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 11. A compound of the formula I according to claim 9, wherein A, R¹, R², R⁴, R⁵ and B are defined as in claim 9 and denote a furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridinyl-C₁₋₂-alkyl or imidazolyl-C₁₋₂-alkyl group which may optionally be substituted in the heteroaryl moiety by one or two C₁₋₃-alkyl groups, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, C₁₋₃-alkyloxy groups, wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, carboxy or C₁₋₃-alkyloxycarbonyl groups, and unless otherwise stated, by the term “heteroaryl group” mentioned hereinbefore in the definitions is meant a monocyclic 5- or 6-membered heteroaryl group, while the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C₁₋₃-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C₁₋₃-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C₁₋₃-alkyl group and two or three nitrogen atoms, and the bond is effected via a nitrogen atom or via a carbon atom, while the alkyl groups contained in the foregoing definitions which have more than two carbon atoms may, unless otherwise stated, be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different, and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions may be wholly or partly replaced by fluorine atoms, or a tautomer or salt thereof.
 12. A compound of the formula I according to claim 1, wherein the group X¹ denotes a methylene group.
 13. A compound of the formula I according to claim 1, wherein the group X¹ denotes a carbonyl group.
 14. A compound of the formula I according to claim 1, wherein the group X³ denotes a methylene group.
 15. A compound of the formula I according to claim 1 wherein the group X³ denotes a carbonyl group.
 16. A compound of the formula I according to claim 1, wherein the group X⁴ denotes an oxygen atom.
 17. A compound of the formula I according to claim 1, wherein the group B denotes the group


18. A compound of the formula I according to claim 1, wherein the group B denotes the group


19. A compound of the formula I according to claim 1, wherein the group B denotes the group


20. A compound of the formula I according to claim 1, wherein the group R⁸ denotes a chlorine atom.
 21. A compound of the formula I according to claim 1, wherein the group R⁸ denotes a bromine atom.
 22. A compound of the formula I according to claim 1, wherein the group R⁸ denotes an ethynyl group.
 23. A compound according to claim 1, having the formula Ia


24. A compound according to claim 1 selected from the group consisting of: (1) 4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-benzamide, (2) 4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxy-ethyl]-3-methyl-benzamide, (8) 4-(azepan-2-on-1-yl)-3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-benzamide, (9) 4-(azepan-2-on-1-yl)-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-trifluoromethyl-benzamide, (10) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide (12) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-3-methyl-4-([1,3]oxazepan-2-on-3-yl)-benzamide, (13) 3-chloro-N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,4]oxazepan-5-on-4-yl)-benzamide, (23) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-([1,3]oxazepan-2-on-3-yl)-3-trifluoromethyl-benzamide, (32) N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethyl]-4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzamide, or a tautomer or salt thereof.
 25. A physiologically acceptable salt of a compound according to claim
 1. 26. A pharmaceutical composition comprising a compound according to claim 1, or a physiologically acceptable salt thereof, together with one or more inert carriers and/or diluents.
 27. A method for inhibiting factor Xa or a related serine protease selected from urokinase, factor VIIa, factor IXa, Factor XIa and factor XIIa which comprises administering an inhibitory amount of a compound in accordance with claim 1 or a physiologically acceptable salt thereof. 